Multiple presentations of pediatric activated PI3K-delta syndrome: a single-center experience in south-central mainland China

Multiple presentations of pediatric activated PI3K-delta syndrome: a single-center experience in south-central mainland China | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Multiple presentations of pediatric activated PI3K-delta syndrome: a single-center experience in south-central mainland China Liang Zhang, Zhijuan Kang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3972529/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 3 You are reading this latest preprint version Abstract Background Activated phosphoinositide 3-kinase delta syndrome causes recurrent respiratory tract infections, lymphoproliferation, autoimmunity, and lymphoma, due to mutations in PI3Kδ subunits, encoded by PIK3CD and PIK3R1 , or PTEN , resulting in APDS1, APDS2, and APDS-L subtypes, respectively. Over 400 cases of APDS have been recognized since 2013; however, reports of pediatric patients from China are relatively limited. Methods Herein, individuals diagnosed with APDS by whole-exome sequencing from a single center in China were retrospectively assessed. Demographic characteristics, disease complications, laboratory data, and genetics were reviewed based on medical records. Results Ten, two, and nine patients with APDS1, APDS2, and APDS-L, respectively, were included. All patients with APDS1 had the c.3061G > A mutation in PIK3CD ; patients with APDS2 had heterozygous c.1425 + 1G > C and c.1425 + 1G > A mutations in PIK3R1 ; and of patients with APDS-L, four had c.388C > T, and the other five had c.697C > T, c.1031delA, c.202T > C, c.640C > T, and c.896dupA mutations in PTEN . Recurrent respiratory tract infections were the most common manifestations in all patients. Neurodevelopmental abnormalities were noted in all patients with APDS-L. Bronchiectasis, chronic lymphoproliferation, and autoimmunity were more common in patients with APDS1 and APDS2. Five patients with APDS1 died from complications, including severe bacterial infection, autoimmune disease, renal failure, and lymphoma. Decreased serum IgG levels, increased IgM levels, B cell lymphopenia, and CD4 lymphopenia were predominant immunologic features in patients with APDS1 and APDS2. Conclusions APDS is a combined immunodeficiency with variable clinical manifestations. Patients with APDS1 and APDS2 had more frequent and severe infections than those with APDS-L. Neurodevelopmental delay was common in patients with APDS-L. APDS can be fatal; appropriate management is required to improved patient outcomes. Phosphatidylinositol 3-Kinases PIK3CD PIK3R1 PTEN Activated PI3K-delta Syndrome Primary immune deficiency Figures Figure 1 Figure 2 Figure 3 Background Phosphatidylinositol 3-kinase (PI3K) signaling has numerous important functions in a broad range of cellular processes, there are multiple PI3K classes (class IA, IB, II, and III), of which, class IA is the predominant type involved in hematopoietic cell signaling [ 1 ]. PI3Kδ is a Class IA PI3K isoform, comprising p85α and p110δ as regulatory and catalytic subunits, respectively, PI3Kδ is predominantly expressed by immune cells and has prominent roles in crucial physiological functions [ 2 ]. The lipid phosphatase, phosphatase and tensin homolog (PTEN), negatively regulates PI3Kδ by terminating its signal propagation [ 3 ]. Tight dynamic regulation of PI3Kδ activity is required to ensure normal immune system function, and germline hyperactivation of PI3Kδ enzyme activity results in a novel monogenic human inborn error of immunity, activated PI3Kδ syndrome (APDS) [ 4 ]. APDS is caused by heterozygous autosomal dominant gain-of-function (GOF) mutations in PIK3CD , which encodes p110δ; loss-of-function (LOF) mutations in PIK3R1 , encoding p85α; or LOF mutations in PTEN , leading to the APDS1, APDS2, and APDS-Like (APDS-L) disease variants, respectively [ 5 ]. Germline GOF variants in p110δ directly increase PI3K pathway activation at the biochemical level [ 6 , 7 ], while p85α LOF mutations result in remarkable loss of PI3Kδ inhibition and consequent p110δ hyperactivation [ 8 , 9 ]. PTEN LOF mutations can result in PTEN hamartoma tumor syndrome (PHTS), which encompasses a variety of conditions predisposing to cancer, such as Cowden and Bannayan-Riley-Ruvalcaba syndromes [ 10 ]. Relative to individuals with APDS1 and APDS2, those with mutations affecting PTEN exhibit relatively lower levels of p110δ hyperactivation; therefore, immunodeficiency was rarely described in earlier reports of patients with PHTS, and recognition of APDS-L occurred relatively recently [ 11 – 13 ]. APDS are now classified as predominantly antibody deficiencies by the International Union of Immunological Societies Expert Committee, because the most common manifestation is recurrent bacterial sinopulmonary infections [ 14 ]. Overall, patients with APDS present with highly variable manifestations, including recurrent respiratory tract infections, bronchiectasis, herpesvirus infections, autoimmunity, non-neoplastic lymphoproliferation, and lymphoma, as well as neurodevelopmental delay [ 5 , 15 , 16 ]. The immunological phenotypes of patients with APDS are variable but typically involve low/normal serum levels of immunoglobulin A (IgA) and IgG; normal or increased IgM; decreased total and naïve CD19 + B cells, with increased transitional B cells; reduced CD4 + helper T cells; normal to increased CD8 + cytotoxic T cells, with an increased senescent proportion; and normal to decreased natural killer cells [ 5 ]. Notably, the susceptibility to various severe infections and abnormalities caused by changes in differentiation and function of T and NK cells suggest that APDS can also cause a combined immunodeficiency phenotype, and patients present with a wide spectrum of clinical symptoms, ranging from mild to fatal [ 17 ]. Numerous cases of APDS have been recognized since 2013; however, diagnosis of the condition is often delayed in mainland China, and the clinical manifestations appear to be more complex [ 18 ]. Here, we reviewed the medical records of clinical manifestations, disease complications, and laboratory features of patients with genetically-defined APDS in a pediatric cohort from a single center, with the aim of further elucidating the complex features of this disorder in Hunan province (south-central mainland China). We describe a high fatality rate, due to delayed diagnosis, and insufficient appropriate and prompt treatment. These findings highlight the need for greater attention among pediatricians in developing countries, to increase early diagnosis and optimal treatment regimens, with the aim of improving patient outcomes. Methods This single-center retrospective study enrolled pediatric patients attending an 1800-bed tertiary care teaching hospital in Hunan province during the period from January 2015 to December 2023. Cases were screened from the database, and clinical information was extracted from electronic medical records. Mutations in PIK3CD , PIK3R1 , and PTEN were identified by whole-exome sequencing and verified by Sanger sequencing. Informed consent for enrollment was obtained from parents. Results Patient characteristics In this retrospective analysis, 21 pediatric patients (17 male) from 21 unrelated families were collected and reviewed. Ten of the patients were diagnosed with the most commonly described GOF mutation in PIK3CD , two with a previously reported splice site mutation in PIK3R1 , and nine with heterozygous mutations in PTEN . One patient with APDS1 and three with APDS-L reported a positive family history (Table 1 ). At the time of data collection, five patients had died at the ages of 8.6 (P1), 14 (P5), 10 (P6), 13 (P7), and 4 (P10) years, after succumbing to complications, including severe bacterial infection resulting in septic shock and disseminated intravascular coagulation (DIC), pulmonary infection and Hodgkin lymphoma, pulmonary infection and severe thrombocytopenia leading to intracranial hemorrhage, pulmonary infection and renal failure, and severe autoimmune hemolytic anemia, respectively; all of the pediatric patients who died were diagnosed with APDS1. Surviving patients had a median age of 5.6 years (range, 1.8–12.3 years) at the time of the latest medical report. Genetic features Of the ten patients with PIK3CD mutations, all had the same p.Glu1021Lys (c.3061G > A) variant, encoding a change in the C-lobe of the p110δ kinase domain. The two patients with PIK3R1 changes had heterozygous c.1425 + 1G > C and c.1425 + 1G > A mutations in a splice donor site, leading to skipping of exon 11. Of the nine patients with PTEN mutations, four had the c.388C > T (p. Arg130X) variant in the phosphatase domain, and the other five had a c.202T > C (p.Tyr68His) variant in the phosphatase domain; c.640C > T (p.Gln214X), c.697C > T (p.Arg233X), and c.896dupA (p.Gln299X) variants in the C2 domain; and a c.1031delA (p.Lys344SerfsX8) variant in the C-terminal domain (Table 2 ). Table 2 Mutation spectrum of patients with APDS Patient Gene Genotype variation Protein variation Zygosity Inheritance Affected domain Type of mutation 1 PIK3CD c.3061G > A p.E1021K Het AD C-Lobe Missense 2 PIK3CD c.3061G > A p.E1021K Het AD C-Lobe Missense 3 PIK3CD c.3061G > A p.E1021K Het AD C-Lobe Missense 4 PIK3CD c.3061G > A p.E1021K Het AD C-Lobe Missense 5 PIK3CD c.3061G > A p.E1021K Het AD C-Lobe Missense 6 PIK3CD c.3061G > A p.E1021K Het AD C-Lobe Missense 7 PIK3CD c.3061G > A p.E1021K Het AD C-Lobe Missense 8 PIK3CD c.3061G > A p.E1021K Het AD C-Lobe Missense 9 PIK3CD c.3061G > A p.E1021K Het AD C-Lobe Missense 10 PIK3CD c.3061G > A p.E1021K Het AD C-Lobe Missense 11 PIK3R1 c.1425 + 1G > A p.434–475del Het AD i-SH2 Splicing 12 PIK3R1 c.1425 + 1G > A p.434–475del Het AD i-SH2 Splicing 13 PTEN c.388C > T p.Arg130X Het AD PH Nonsense 14 PTEN c.388C > T p.Arg130X Het AD PH Nonsense 15 PTEN c.697C > T p.Arg233X Het AD C2 Nonsense 16 PTEN c.388C > T p.Arg130X Het AD PH Nonsense 17 PTEN c.202T>C p.Tyr68His Het AD PH Missense 18 PTEN c.388C > T p.Arg130X Het AD PH Nonsense 19 PTEN c.1031delA p.K344Sfs*8 Het AD C-tail Frameshift 20 PTEN c.640C>T p.Q214X Het AD C2 Nonsense 21 PTEN c.896dupA p.E299X Het AD C2 Frameshift Infectious complications Recurrent upper respiratory tract infections were described in all patients (Figure. 1A), while sinusitis and pneumonia occurred in all patients with APDS1 and APDS2, and were detected in one (11.1%) and five (55.5%) patients in the APDS-L group, respectively. Of patients with APDS1, otitis media and tonsillitis were recorded in 60% and 50%, respectively, and these conditions occurred in both patients with APDS2. Only two (22.2%) patients with APDS-L presented with tonsillitis. While bronchiectasis was noted on chest computed tomography (CT) scans in three (30.0%) patients with APDS1, one with APDS2, and none of those with APDS-L (Table 1 ). Digestive tract infections were present in four (40.0%) patients with APDS1, one with APDS2, and none with APDS-L (Figure. 1A). Similarly, septicemia was identified in four (40.0%) patients with APDS1, one with APDS2, and none with APDS-L. Pulmonary fungal infections were identified by galactomannan assay in bronchoalveolar lavage fluid (BALF) and peripheral blood samples, or by metagenomic next-generation sequencing of BALF, and were detected in six (60.0%) patients with APDS1, one with APDS2, and none with APDS-L. Bacillus Calmette-Guérin (BCG)-osis (10.0%), tuberculosis (10.0%), meningitis (10.0%), skin abscess (20.0%), peritonitis (20.0%), pleuritis/empyema (40.0%), persistent herpesvirus infection (70.0%), urinary tract infection (10.0%), appendicitis (10.0%), localized warts (10.0%), and hepatitis (10.0%) were described only in patients with APDS1 (Figure. 1A); notably, the occurrence of severe medical conditions that required hospitalization was significantly more frequent in the APDS1 and APDS2 groups than in patients with APDS-L. Of the pathogenic organisms identified in patients with APDS, Haemophilus influenzae , Streptococcus pneumoniae , and Mycoplasma pneumoniae were the most common bacteria and were most frequently isolated from patients with APDS1 (Figure. 1B); Staphylococcus aureus , Staphylococcus epidermidis , Staphylococcus hominis , Stenotrophomonas maltophilia , Burkholderia cepacia , Pseudomonas aeruginosa , Escherichia coli , Chlamydia pneumoniae , and Achromobacter species were also sporadically reported. Aspergillus species were the most common pathogenic fungi, described in five (50.0%) patients with APDS1, followed by Candida albicans in one (10.0%) patient with APDS1 and in one with APDS2, and Candida tropicalis in one (10.0%) patient with APDS1; no fungal species were identified in patients with APDS-L. The most common viral susceptibility was to herpesviruses, with Epstein Barr Virus (EBV) viremia most persistently detected, occurring in six (60.0%) patients with APDS1, one of whom (P5) progressed to EBV-positive lymphoma. Cytomegalovirus viremia was detected in one (10.0%) patient with APDS1. History of other herpesvirus infections was reported in two patients, including herpes simplex virus in one patient with APDS-L and varicella zoster virus in one patient with APDS1. History of infection with other viruses was also reported, including one patient with APDS1 (P10) with human papillomavirus and hepatitis B virus; respiratory syncytial virus in two patients with APDS-L; parainfluenza virus in two patients with APDS-L; influenza virus in one patient with APDS2; rubella virus in one patient with APDS1; enterovirus type 71 in one patient with APDS1; and adenovirus in three patients, including one with each of APDS1, APDS2, and APDS-L. One patient (P1) presented with invasive S. pneumoniae septicemia and peritonitis, leading to septic shock, DIC, and death. One patient (P7) had localized BCG-induced granulomatous inflammation after vaccination and developed a tuberculosis infection at 2 years old. One patient (P1) underwent resection of an abscess in the epiglottis, one (P5) was treated by laparoscopic appendectomy, and one (P6) underwent closed thoracic drainage. Lymphoproliferative and hematologic complications Most patients with APDS1 (90.0%) and both of those with APDS2 presented with chronic lymphadenopathy, splenomegaly, and/or hepatomegaly on physical examination, ultrasonography, and/or CT, while these features were not recorded in patients with APDS-L (Figure. 2A). Mucosal nodular lymphoid hyperplasia was visualized endoscopically as cobblestone-like plaques or polyps in six (60.0%) patients with APDS1 and one with APDS2. One patient with APDS1 (P5) progressed to Hodgkin lymphoma, with scattered EBV-positive cells present in the cervical and axillary lymph nodes and mucosal-associated lymphoid tissue in the ileocecal region. Six (60.0%) patients with APDS1, one with APDS2, and two (22.2%) with APDS-L experienced hemolytic anemia, including four (40.0%) with APDS1 and one with APDS-L who had Evans syndrome. Further, one patient with APDS1 (P10) died from severe autoimmune hemolytic anemia. Four (40.0%) patients with APDS1 had lymphopenia, three of whom also had leucopenia. Neutropenia and lymphopenia were each observed in one patient with APDS-L. Autoimmune, allergic, and inflammatory features Three (30.0%) patients with APDS1 (P5, P6, and P7) had systemic lupus erythematosus (SLE)-like features, including positive antinuclear antibodies, such as antibodies against Sm, double-stranded DNA, SSA/Ro52, nucleosomes, or histones, with diminished levels of the serum complement components, C3 and C4 (Figure. 2A). Three (30.0%) patients (P4, P7, P8) had renal involvement, including proteinuria and gross hematuria, together with massive proteinuria and renal failure, and microscopic hematuria, respectively; among these, P7 underwent kidney biopsy for proliferative sclerosing glomerulonephritis. Three patients with APDS1 (P2, P3, P6) presented with autoimmune thyroiditis, juvenile arthritis, and autoimmune hepatitis, respectively, while autoimmune organ involvement was absent in patients with APDS-L. Five (50.0%) patients with APDS1 and three (33.3%) with APDS-L had a history of food allergies (Figure. 2A). Five (50.0%) patients with APDS1, one with APDS2, and three (33.3%) with APDS-L were diagnosed with asthma, while three (30.0%) patients with APDS1 presented with chronic eczema, and one (10.0%) patient with APDS1 and one (11.1%) with APDS-L had atopic dermatitis. Four (40.0%) patients with APDS1 and one with APDS2 had enteropathy/chronic diarrhea (Table I), while three (30.0%) patients with APDS1 (P2, P5, P7) were diagnosed with inflammatory bowel disease by endoscopic biopsy (Figure. 2A). Neurological, developmental, and other features Macrocrania or motor and language development delay were the initial clinical presentations for consultation in all patients with APDS-L, three of whom (P13, P14, P17) were diagnosed with autism, and one (P15) had a history of seizures (Figure. 2B). Mental retardation was also detected in two (20.0%) patients with APDS1 and both with APDS2. A history of failure to thrive was noted in the majority of patients with APDS1 (90.0%) and APDS2 (100.0%), while this feature was reported in only four (44.4%) patients with APDS-L. Other conditions noted included two (P7, P16) patients with remaining patent foramen ovale; two (P2, P11) with rickets; three (P16, P19, P20) with congenital hypothyroidism; one (P11) with a history of recurrent intussusceptions; one (P20) with bilateral squints; one (P5) with bilateral cryptorchidism; one (P15) with bilateral hernias; one (P21) with bilateral hypoplastic kidneys; one (P15) with laryngomalacia; one (P19) with thumb polydactyly; one (P21) with limb length discrepancy and bilateral hip dislocation; and two (P19, P21) with congenital verrucous nevus and hamartomas, such as hemangiomas and lipomas. Immunological laboratory characteristics Basic immunological laboratory results of the patients at the time of their first evaluation in our hospital are presented in Fig. 3 ; these were not evaluated in most (6 of 9) patients with APDS-L. Reduced IgA (60.0%) and increased IgM (70.0%) levels were common in patients with APDS1, while one patient (P4) had reduced IgM levels, and two had normal IgM levels. IgG levels were variable in patients with APDS1, with four (40.0%) having reduced total IgG levels that were too low to be detected, three (30.0%) having normal IgG levels, and three (30.0%) having high IgG levels. Both patients with APDS2 had reduced IgG and IgA levels, and decreased IgM levels. Of the three cases with APDS-L who underwent testing, one (P15) had reduced IgM levels, one (P16) had reduced IgA levels, and one (P21) had elevated IgM levels; significantly decreased IgG levels were not noted. In this cohort, six (60.0%) patients with APDS1 developed B cell lymphopenia, and nine (90.0%) with APDS1 had CD4 T cell lymphopenia. An inverted CD4/CD8 ratio was present in 80% of patients with APDS1 and both of those with APDS2. Discussion A high degree of variability in the clinical features has been observed in patients with APDS, and numerous cases presenting with a much more complex phenotype, comprising combined immunodeficiency and immune dysregulation, have been reported [ 5 ]. Here, we present a retrospective analysis of the clinical features in patients with APDS from a single-center in south-central mainland China. This is the third cohort of pediatric patients with APDS from mainland China reported [ 18 , 19 ]. In our center, recurrent upper respiratory tract infections were described in all patients with the three disease subtypes, while sinusitis and pneumonia were more frequent in patients with APDS1 in our cohort compared with previous studies, partly due to lack of immunoglobulin replacement and antibiotic prophylaxis treatment. Episodes of recurrent bacterial sinopulmonary infections requiring hospitalization for intravenous therapy and medical support, which started early in life (< 1 year old), were significantly more frequent in the APDS1 and APDS2 groups than in the APDS-L group. Further, the incidence of bronchiectasis demonstrated by CT, which is a key feature of APDS, was 30% among patients with APDS1 before 7 years old but was not detected in the APDS-L group. Consistent with these findings, analysis of a series of patients with PHTS revealed that sinopulmonary infections were not a major clinical feature [ 11 – 13 ]. By comparison, other infections, including pleuritis, empyema, and peritonitis, were also more common in our cohort, while ocular and urinary tract infections were sporadically documented, which might be ignored by physicians in our center [ 15 , 16 , 20 ]. In accordance with previous reports [ 16 , 17 ], encapsulated bacteria, including S. pneumoniae and H. influenzae , were the most frequent bacterial pathogens isolated from patients in this study, followed by M. pneumoniae . Invasive bacterial infections were reported in five cases, indicating more complicated and frequent infections in our patients than previously reported. Mycobacterial infection was described in only one patient with APDS1, who developed local granulomas and tuberculosis after BCG vaccine, similar to previous reports [ 16 – 18 , 20 ]. Fungal pathogens, such as Aspergillus , were detected in a significant proportion of patients with APDS1 and were more frequent in our cohort than previously described [ 16 – 18 , 20 – 22 ]. History of EBV infection was also relatively common in the APDS1 group but not described in the APDS2 and APDS-L groups. Lymphoproliferative diseases, including lymphadenopathy, hepatomegaly, splenomegaly, and nodular mucosal lymphoid hyperplasia, another emblematic clinical manifestations, were commonplace in the APDS1 and APDS2 groups but were not detected by physical examination or directly discovered on ultrasound examination in patients with APDS-L. This phenomenon is similar to that described in a previously reported series of patients with PHTS, where lymphoid hyperplasia was apparently rare [ 11 – 13 ]. In addition to benign lymphoproliferation, patients with APDS are also at increased risk of malignancies, primarily lymphomas [ 16 ]. One patient with APDS1 progressed to Hodgkin lymphoma associated with persistent EBV infection at 9 years old, consistent with previous reports that history of lymphoma is significantly associated with EBV but not other herpesviruses [ 20 ]. Patients with APDS are prone to coexistence of various autoimmune and autoinflammatory conditions, including hematologic, rheumatologic, gastrointestinal, and endocrine disorders, such as cytopenia, arthritis, colitis, enteropathy, and thyroiditis, respectively, as well as dermatologic disorders, which were more frequent in the APDS1 group in our cohort. Autoimmune hemolytic anemia were the most frequent autoimmune complications. Allergic diseases, including asthma, eczema, and food allergy, were also prevalent, as mentioned in other cohorts [ 20 ]. Glomerulosclerosis was detected in one patient with APDS-1, with SLE-like manifestations, which is an atypical pathological presentation of lupus nephritis, consistent with other reports [ 16 , 23 ]. Proteinuria, which dominates renal involvement in patients with APDS [ 23 ], appears to be related to a mechanism whereby hyperactivated PI3K-Akt signaling in kidney podocytes sensitizes them to injury and apoptosis through endoplasmic reticulum stress [ 24 ]. Patients with APDS have a variable incidence of neurological and developmental disorders [ 10 , 15 , 16 ]. In our cohort, neurodevelopmental delay and/or macrocrania were prominent features in the APDS-L group and were the primary abnormalities, attracting considerable attention. A large burden of neurological diseases, including seizures, motor and language development delay, mental retardation, and autism, was present. The high frequency of neurological and developmental involvement is likely due to high PI3K levels in the central nervous system and crosstalk between nervous and immune systems [ 25 – 28 ]. The immunological phenotype hallmarks in patients initially diagnosed with APDS include lymphopenia, reduced B cell count, inverted CD4/CD8 ratio, CD8 T cell senescence, and variable hypogammaglobulinemia [ 5 ]. CD4 T cell lymphopenia and inverted CD4/CD8 ratio was the most common situation in the APDS1 group, followed by B cell lymphopenia, which is somewhat different from other reports. Low IgA and increased IgM serum levels were prevalent in the APDS1 and APDS2 groups, serum IgG levels were undetectable in APDS2 while broadly normal or elevated in APDS1, notably those presenting with complex complications such as autoimmune disorders. It is noteworthy that these superficial immune function evaluations were frequently not conducted in patients with APDS-L in our cohort. No treatment guidelines for APDS are yet available, and management is principally implemented by addressing clinical symptoms, complications, and medical conditions. Several therapeutic modalities have been employed, including conventional immunodeficiency therapies, such as immunoglobulin replacement, antibiotic prophylaxis, and immunosuppression, as well as more targeted therapies, such as mTOR inhibition with sirolimus and selective PI3Kδ inhibitors, or hematopoietic stem cell transplant [ 5 , 23 , 29 ]; however, in general, mortality and complication rates were high in our cohort, predominantly due to diagnostic delay and lack of standard procedures for diagnosis and treatment. Hence, there is an urgent need for consensus and guideline statements. We describes clinical phenotypes and disease outcomes of a large cohort of pediatric APDS patients from a single-center in developing countries, and further evaluates differences between subtypes. This study has some obvious limitations. Specifically, it was a retrospective observational study conducted at a single center; the number of included pediatric patients was small, particularly in the APDS2 group; and follow-up time was relatively short, all of which inherently limit analytical power. Furthermore, owing to lack of recognition, the medical records often lacked detailed and comprehensive investigations. Additionally, due to the limitations of laboratory conditions, extensive analyses of immunological characteristics and functions were lacking. Conclusion In conclusion, our review indicates highly heterogeneous clinical features among patients with APDS, with those in the ADPS1 and APDS2 groups presenting with more severe immunodeficiency and a higher frequency of developmental delay than patients with APDS-L, while other phenotypes, particularly macrocrania and motor and language development delay, were more frequent in patients with APDS-L. Abbreviations APDS activated phosphoinositide 3–kinase d syndrome APDS1 activated phosphoinositide 3–kinase d syndrome caused by mutations in PIK3CD APDS2 activated phosphoinositide 3–kinase d syndrome caused by mutations in PIK3R1 APDS-L activated phosphoinositide 3–kinase d syndrome-like caused by mutations in PTEN BALF bronchoalveolar lavage fluid BCG Bacillus Calmette-Guérin EBV Epstein Barr Virus GOF gain-of-function LOF loss-of-function PI3K phosphatidylinositol 3-kinase PI3Kδ PI3Kδ Phosphoinositide 3-kinase delta PTEN phosphatase and tensin homolog SLE systemic lupus erythematosus Declarations Ethics Approval This study was performed after obtaining written informed consent from the patients’ guardians, consistent with the Declaration of Helsinki. This study was approved by the Medical Ethics Committee of Hunan Children’s Hospital. Consent to Participate Informed consent was obtained from the patients and their parents. Consent to Publish Written informed consent was obtained from all participants for the publication of any potentially identifable images or data included in this manuscript. Competing Interests The authors declare no conflicts of interest. Data availability The authors declare that all data supporting the findings of this study are available within the article. Author Contributions LZ and ZJK designed the study, performed clinical investigations, collected the data, and wrote the manuscript. All authors reviewed the manuscript prior to submission. Funding This work was supported by the Clinical Medical Technology Innovation and Guidance Project Hunan Province (grant number: 2021SK50502), by the Specialized Diseases Cohort Study Program of Hunan Children’s Hospital (grant number: 2021ZBDL03), and by the special fund of the Hunan provincial key laboratory of pediatric orthopedics (grant number: 2023TP1019). 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Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study. J Allergy Clin Immunol. 2016;138(1):210–218e9. 10.1016/j.jaci.2016.03.022 . Coulter TI, Chandra A, Bacon CM, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597–606e4. 10.1016/j.jaci.2016.06.021 . Brodsky NN, Lucas CL. Infections in activated PI3K delta syndrome (APDS). Curr Opin Immunol. 2021;72:146–57. 10.1016/j.coi.2021.04.010 . Qiu L, Wang Y, Tang W, et al. Activated Phosphoinositide 3-Kinase δ Syndrome: a Large Pediatric Cohort from a Single Center in China. J Clin Immunol. 2022;42(4):837–50. 10.1007/s10875-022-01218-4 . Wang Y, Wang W, Liu L, et al. Report of a Chinese Cohort with Activated Phosphoinositide 3-Kinase δ Syndrome. J Clin Immunol. 2018;38(8):854–63. 10.1007/s10875-018-0568-x . Oh J, Garabedian E, Fuleihan R, Cunningham-Rundles C. Clinical Manifestations and Outcomes of Activated Phosphoinositide 3-Kinase δ Syndrome from the USIDNET Cohort. J Allergy Clin Immunol Pract. 2021;9(11):4095–102. 10.1016/j.jaip.2021.07.044 . Tessarin G, Rossi S, Baronio M, et al. Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients. J Clin Med. 2020;9(10):3335. 10.3390/jcm9103335 . Fekrvand S, Delavari S, Chavoshzadeh Z, et al. The First Iranian Cohort of Pediatric Patients with Activated Phosphoinositide 3-Kinase-δ (PI3Kδ) Syndrome (APDS). Immunol Invest. 2022;51(3):644–59. 10.1080/08820139.2020.1863982 . Dimitrova D, Nademi Z, Maccari ME, et al. International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome. J Allergy Clin Immunol. 2022;149(1):410–421e7. 10.1016/j.jaci.2021.04.036 . Garner KL, Betin VMS, Pinto V, et al. Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress. Sci Rep. 2018;8(1):3902. 10.1038/s41598-018-22233-9 . Eickholt BJ, Ahmed AI, Davies M, et al. Control of axonal growth and regeneration of sensory neurons by the p110delta PI 3-kinase. PLoS ONE. 2007;2(9):e869. 10.1371/journal.pone.0000869 . Costa-Mattioli M, Monteggia LM. mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat Neurosci. 2013;16(11):1537–43. 10.1038/nn.3546 . Yehia L, Ngeow J, Eng C. PTEN-opathies: from biological insights to evidence-based precision medicine. J Clin Invest. 2019;129(2):452–64. 10.1172/JCI121277 . Serra I, Manusama OR, Kaiser FMP, et al. Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model. Brain Behav Immun Health. 2021;18:100377. 10.1016/j.bbih.2021.100377 . Rao VK, Webster S, Šedivá A, et al. A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome. Blood. 2023;141(9):971–83. 10.1182/blood.2022018546 . Table 1 Table 1 is available in the Supplementary Files section. Supplementary Files Table1.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 03 Mar, 2024 Editor assigned by journal 22 Feb, 2024 First submitted to journal 19 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3972529","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":276097008,"identity":"ee69792e-6e48-4d5d-a0d9-b338e10e3bbf","order_by":0,"name":"Liang Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzUlEQVRIiWNgGAWjYBACNv7+D8Z/Kmzs+BkOHyBOC5/EAYMCnjNpyZKNxxKI0yLHkGDwgbftEOOGw2cMiHQYw4HEDRJnDjBLtp35eOMNg52cbgMhLcwNhw0MKu7w8fOc3Ww5hyHZ2OwAQVsOthkknHnGLDnj7DZpHqCd2whrSWb/cbDtMOOG+2+eEasljcGwEaTlwBk2IrVInGEwZgAFcsMxY8s5BkT4Rb6/B6gFEpUPb7ypsJMjqAUFSPAQGTXIWkjVMQpGwSgYBSMCAACFCkeu+f5GRwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-5954-5828","institution":"Hunan Children's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Liang","middleName":"","lastName":"Zhang","suffix":""},{"id":276097009,"identity":"235a7cb5-7099-4f99-a4af-8566a0bc60f8","order_by":1,"name":"Zhijuan Kang","email":"","orcid":"","institution":"Hunan Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhijuan","middleName":"","lastName":"Kang","suffix":""}],"badges":[],"createdAt":"2024-02-20 10:37:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3972529/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3972529/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52106196,"identity":"86cb0146-cc10-4078-98c9-a47b973e4518","added_by":"auto","created_at":"2024-03-06 19:36:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1549519,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMain infectious complications and spectrum of pathogenic organisms identified in patients with APDS.\u003c/strong\u003e A Infectious manifestations were identified separately for patients with APDS1, APDS2, and APDS-L. Red and light gray boxes indicate the presence or absence of a complication, respectively. B Identified pathogenic organisms were isolated from patients. Red and light gray boxes indicate the presence or absence of an identified organism, respectively.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3972529/v1/96894a8a6c81b4e8f091a148.png"},{"id":52106198,"identity":"62f8b612-1ce6-4a74-964f-0bfb1d79ca15","added_by":"auto","created_at":"2024-03-06 19:36:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1022539,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNoninfective features in patients with APDS.\u003c/strong\u003e A Lymphoproliferative, hematologic, autoimmune, allergic, and inflammatory features in patients with APDS. B Neurological, developmental, and other features in patients with APDS. Red and light gray boxes indicate the presence or absence of a complication, respectively.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3972529/v1/1a0f9964fd62a9f44f496b77.png"},{"id":52106199,"identity":"e654a4d2-b055-4297-9e2f-4a5a52bce959","added_by":"auto","created_at":"2024-03-06 19:36:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":421683,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSummary of basic immunological laboratory results of patients with APDS.\u003c/strong\u003e In the APDS1 group, CD4-T cell lymphopenia and inverted CD4/CD8 ratio was the most common picture, followed by B cell lymphopenia and increased IgM serum levels. Red, yellow, and green boxes indicate increased, decreased, or normal laboratory test results, respectively; light gray boxes indicate absence of a laboratory test; purple and blue boxes indicate the presence or absence, respectively, of a reversed CD4/CD8 ratio.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3972529/v1/a5af60a3f7d71734c9bac07b.png"},{"id":52107163,"identity":"7d03cc91-a7d8-413a-9efc-e1b36acbc76c","added_by":"auto","created_at":"2024-03-06 19:52:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2149586,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3972529/v1/1a8d5213-35d6-4094-92b6-0bfae04bf3ac.pdf"},{"id":52106725,"identity":"1ef08c6f-7511-42ee-9c14-ebfccacb3e3f","added_by":"auto","created_at":"2024-03-06 19:44:20","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":32364,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3972529/v1/e7fb1d9bcd42ccfa1a1d81ac.docx"}],"financialInterests":"","formattedTitle":"Multiple presentations of pediatric activated PI3K-delta syndrome: a single-center experience in south-central mainland China","fulltext":[{"header":"Background","content":"\u003cp\u003ePhosphatidylinositol 3-kinase (PI3K) signaling has numerous important functions in a broad range of cellular processes, there are multiple PI3K classes (class IA, IB, II, and III), of which, class IA is the predominant type involved in hematopoietic cell signaling [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. PI3Kδ is a Class IA PI3K isoform, comprising p85α and p110δ as regulatory and catalytic subunits, respectively, PI3Kδ is predominantly expressed by immune cells and has prominent roles in crucial physiological functions [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The lipid phosphatase, phosphatase and tensin homolog (PTEN), negatively regulates PI3Kδ by terminating its signal propagation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Tight dynamic regulation of PI3Kδ activity is required to ensure normal immune system function, and germline hyperactivation of PI3Kδ enzyme activity results in a novel monogenic human inborn error of immunity, activated PI3Kδ syndrome (APDS) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. APDS is caused by heterozygous autosomal dominant gain-of-function (GOF) mutations in \u003cem\u003ePIK3CD\u003c/em\u003e, which encodes p110δ; loss-of-function (LOF) mutations in \u003cem\u003ePIK3R1\u003c/em\u003e, encoding p85α; or LOF mutations in \u003cem\u003ePTEN\u003c/em\u003e, leading to the APDS1, APDS2, and APDS-Like (APDS-L) disease variants, respectively [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGermline GOF variants in p110δ directly increase PI3K pathway activation at the biochemical level [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], while p85α LOF mutations result in remarkable loss of PI3Kδ inhibition and consequent p110δ hyperactivation [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. PTEN LOF mutations can result in PTEN hamartoma tumor syndrome (PHTS), which encompasses a variety of conditions predisposing to cancer, such as Cowden and Bannayan-Riley-Ruvalcaba syndromes [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Relative to individuals with APDS1 and APDS2, those with mutations affecting PTEN exhibit relatively lower levels of p110δ hyperactivation; therefore, immunodeficiency was rarely described in earlier reports of patients with PHTS, and recognition of APDS-L occurred relatively recently [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAPDS are now classified as predominantly antibody deficiencies by the International Union of Immunological Societies Expert Committee, because the most common manifestation is recurrent bacterial sinopulmonary infections [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Overall, patients with APDS present with highly variable manifestations, including recurrent respiratory tract infections, bronchiectasis, herpesvirus infections, autoimmunity, non-neoplastic lymphoproliferation, and lymphoma, as well as neurodevelopmental delay [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The immunological phenotypes of patients with APDS are variable but typically involve low/normal serum levels of immunoglobulin A (IgA) and IgG; normal or increased IgM; decreased total and na\u0026iuml;ve CD19\u003csup\u003e+\u003c/sup\u003e B cells, with increased transitional B cells; reduced CD4\u003csup\u003e+\u003c/sup\u003e helper T cells; normal to increased CD8\u003csup\u003e+\u003c/sup\u003e cytotoxic T cells, with an increased senescent proportion; and normal to decreased natural killer cells [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Notably, the susceptibility to various severe infections and abnormalities caused by changes in differentiation and function of T and NK cells suggest that APDS can also cause a combined immunodeficiency phenotype, and patients present with a wide spectrum of clinical symptoms, ranging from mild to fatal [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNumerous cases of APDS have been recognized since 2013; however, diagnosis of the condition is often delayed in mainland China, and the clinical manifestations appear to be more complex [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Here, we reviewed the medical records of clinical manifestations, disease complications, and laboratory features of patients with genetically-defined APDS in a pediatric cohort from a single center, with the aim of further elucidating the complex features of this disorder in Hunan province (south-central mainland China).\u003c/p\u003e \u003cp\u003eWe describe a high fatality rate, due to delayed diagnosis, and insufficient appropriate and prompt treatment. These findings highlight the need for greater attention among pediatricians in developing countries, to increase early diagnosis and optimal treatment regimens, with the aim of improving patient outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis single-center retrospective study enrolled pediatric patients attending an 1800-bed tertiary care teaching hospital in Hunan province during the period from January 2015 to December 2023. Cases were screened from the database, and clinical information was extracted from electronic medical records. Mutations in \u003cem\u003ePIK3CD\u003c/em\u003e, \u003cem\u003ePIK3R1\u003c/em\u003e, and \u003cem\u003ePTEN\u003c/em\u003e were identified by whole-exome sequencing and verified by Sanger sequencing. Informed consent for enrollment was obtained from parents.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eIn this retrospective analysis, 21 pediatric patients (17 male) from 21 unrelated families were collected and reviewed. Ten of the patients were diagnosed with the most commonly described GOF mutation in \u003cem\u003ePIK3CD\u003c/em\u003e, two with a previously reported splice site mutation in \u003cem\u003ePIK3R1\u003c/em\u003e, and nine with heterozygous mutations in \u003cem\u003ePTEN\u003c/em\u003e. One patient with APDS1 and three with APDS-L reported a positive family history (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). At the time of data collection, five patients had died at the ages of 8.6 (P1), 14 (P5), 10 (P6), 13 (P7), and 4 (P10) years, after succumbing to complications, including severe bacterial infection resulting in septic shock and disseminated intravascular coagulation (DIC), pulmonary infection and Hodgkin lymphoma, pulmonary infection and severe thrombocytopenia leading to intracranial hemorrhage, pulmonary infection and renal failure, and severe autoimmune hemolytic anemia, respectively; all of the pediatric patients who died were diagnosed with APDS1. Surviving patients had a median age of 5.6 years (range, 1.8\u0026ndash;12.3 years) at the time of the latest medical report.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eGenetic features\u003c/h2\u003e \u003cp\u003eOf the ten patients with \u003cem\u003ePIK3CD\u003c/em\u003e mutations, all had the same p.Glu1021Lys (c.3061G\u0026thinsp;\u0026gt;\u0026thinsp;A) variant, encoding a change in the C-lobe of the p110δ kinase domain. The two patients with \u003cem\u003ePIK3R1\u003c/em\u003e changes had heterozygous c.1425\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;C and c.1425\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A mutations in a splice donor site, leading to skipping of exon 11. Of the nine patients with \u003cem\u003ePTEN\u003c/em\u003e mutations, four had the c.388C\u0026thinsp;\u0026gt;\u0026thinsp;T (p. Arg130X) variant in the phosphatase domain, and the other five had a c.202T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Tyr68His) variant in the phosphatase domain; c.640C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Gln214X), c.697C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg233X), and c.896dupA (p.Gln299X) variants in the C2 domain; and a c.1031delA (p.Lys344SerfsX8) variant in the C-terminal domain (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMutation spectrum of patients with APDS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGenotype variation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProtein variation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZygosity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eInheritance\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAffected domain\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eType of mutation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePIK3CD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.3061G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.E1021K\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC-Lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePIK3CD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.3061G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.E1021K\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC-Lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePIK3CD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.3061G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.E1021K\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC-Lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePIK3CD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.3061G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.E1021K\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC-Lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePIK3CD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.3061G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.E1021K\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC-Lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePIK3CD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.3061G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.E1021K\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC-Lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePIK3CD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.3061G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.E1021K\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC-Lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePIK3CD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.3061G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.E1021K\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC-Lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePIK3CD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.3061G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.E1021K\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC-Lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePIK3CD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.3061G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.E1021K\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC-Lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePIK3R1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1425\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.434\u0026ndash;475del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ei-SH2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSplicing\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePIK3R1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1425\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.434\u0026ndash;475del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ei-SH2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSplicing\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePTEN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.388C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.Arg130X\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePTEN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.388C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.Arg130X\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePTEN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.697C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.Arg233X\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePTEN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.388C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.Arg130X\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePTEN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.202T\u0026gt;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.Tyr68His\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePTEN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.388C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.Arg130X\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePTEN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1031delA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.K344Sfs*8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC-tail\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePTEN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.640C\u0026gt;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.Q214X\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePTEN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.896dupA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.E299X\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eInfectious complications\u003c/h2\u003e \u003cp\u003eRecurrent upper respiratory tract infections were described in all patients (Figure. 1A), while sinusitis and pneumonia occurred in all patients with APDS1 and APDS2, and were detected in one (11.1%) and five (55.5%) patients in the APDS-L group, respectively. Of patients with APDS1, otitis media and tonsillitis were recorded in 60% and 50%, respectively, and these conditions occurred in both patients with APDS2. Only two (22.2%) patients with APDS-L presented with tonsillitis. While bronchiectasis was noted on chest computed tomography (CT) scans in three (30.0%) patients with APDS1, one with APDS2, and none of those with APDS-L (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Digestive tract infections were present in four (40.0%) patients with APDS1, one with APDS2, and none with APDS-L (Figure. 1A). Similarly, septicemia was identified in four (40.0%) patients with APDS1, one with APDS2, and none with APDS-L. Pulmonary fungal infections were identified by galactomannan assay in bronchoalveolar lavage fluid (BALF) and peripheral blood samples, or by metagenomic next-generation sequencing of BALF, and were detected in six (60.0%) patients with APDS1, one with APDS2, and none with APDS-L. Bacillus Calmette-Gu\u0026eacute;rin (BCG)-osis (10.0%), tuberculosis (10.0%), meningitis (10.0%), skin abscess (20.0%), peritonitis (20.0%), pleuritis/empyema (40.0%), persistent herpesvirus infection (70.0%), urinary tract infection (10.0%), appendicitis (10.0%), localized warts (10.0%), and hepatitis (10.0%) were described only in patients with APDS1 (Figure. 1A); notably, the occurrence of severe medical conditions that required hospitalization was significantly more frequent in the APDS1 and APDS2 groups than in patients with APDS-L.\u003c/p\u003e \u003cp\u003eOf the pathogenic organisms identified in patients with APDS, \u003cem\u003eHaemophilus influenzae\u003c/em\u003e, \u003cem\u003eStreptococcus pneumoniae\u003c/em\u003e, and \u003cem\u003eMycoplasma pneumoniae\u003c/em\u003e were the most common bacteria and were most frequently isolated from patients with APDS1 (Figure. 1B); \u003cem\u003eStaphylococcus aureus\u003c/em\u003e, \u003cem\u003eStaphylococcus epidermidis\u003c/em\u003e, \u003cem\u003eStaphylococcus hominis\u003c/em\u003e, \u003cem\u003eStenotrophomonas maltophilia\u003c/em\u003e, \u003cem\u003eBurkholderia cepacia\u003c/em\u003e, \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e, \u003cem\u003eEscherichia coli\u003c/em\u003e, \u003cem\u003eChlamydia pneumoniae\u003c/em\u003e, and \u003cem\u003eAchromobacter\u003c/em\u003e species were also sporadically reported. \u003cem\u003eAspergillus\u003c/em\u003e species were the most common pathogenic fungi, described in five (50.0%) patients with APDS1, followed by \u003cem\u003eCandida albicans\u003c/em\u003e in one (10.0%) patient with APDS1 and in one with APDS2, and \u003cem\u003eCandida tropicalis\u003c/em\u003e in one (10.0%) patient with APDS1; no fungal species were identified in patients with APDS-L. The most common viral susceptibility was to herpesviruses, with Epstein Barr Virus (EBV) viremia most persistently detected, occurring in six (60.0%) patients with APDS1, one of whom (P5) progressed to EBV-positive lymphoma. Cytomegalovirus viremia was detected in one (10.0%) patient with APDS1. History of other herpesvirus infections was reported in two patients, including herpes simplex virus in one patient with APDS-L and varicella zoster virus in one patient with APDS1. History of infection with other viruses was also reported, including one patient with APDS1 (P10) with human papillomavirus and hepatitis B virus; respiratory syncytial virus in two patients with APDS-L; parainfluenza virus in two patients with APDS-L; influenza virus in one patient with APDS2; rubella virus in one patient with APDS1; enterovirus type 71 in one patient with APDS1; and adenovirus in three patients, including one with each of APDS1, APDS2, and APDS-L.\u003c/p\u003e \u003cp\u003eOne patient (P1) presented with invasive \u003cem\u003eS. pneumoniae\u003c/em\u003e septicemia and peritonitis, leading to septic shock, DIC, and death. One patient (P7) had localized BCG-induced granulomatous inflammation after vaccination and developed a tuberculosis infection at 2 years old. One patient (P1) underwent resection of an abscess in the epiglottis, one (P5) was treated by laparoscopic appendectomy, and one (P6) underwent closed thoracic drainage.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eLymphoproliferative and hematologic complications\u003c/h2\u003e \u003cp\u003eMost patients with APDS1 (90.0%) and both of those with APDS2 presented with chronic lymphadenopathy, splenomegaly, and/or hepatomegaly on physical examination, ultrasonography, and/or CT, while these features were not recorded in patients with APDS-L (Figure. 2A). Mucosal nodular lymphoid hyperplasia was visualized endoscopically as cobblestone-like plaques or polyps in six (60.0%) patients with APDS1 and one with APDS2. One patient with APDS1 (P5) progressed to Hodgkin lymphoma, with scattered EBV-positive cells present in the cervical and axillary lymph nodes and mucosal-associated lymphoid tissue in the ileocecal region.\u003c/p\u003e \u003cp\u003eSix (60.0%) patients with APDS1, one with APDS2, and two (22.2%) with APDS-L experienced hemolytic anemia, including four (40.0%) with APDS1 and one with APDS-L who had Evans syndrome. Further, one patient with APDS1 (P10) died from severe autoimmune hemolytic anemia. Four (40.0%) patients with APDS1 had lymphopenia, three of whom also had leucopenia. Neutropenia and lymphopenia were each observed in one patient with APDS-L.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAutoimmune, allergic, and inflammatory features\u003c/h2\u003e \u003cp\u003eThree (30.0%) patients with APDS1 (P5, P6, and P7) had systemic lupus erythematosus (SLE)-like features, including positive antinuclear antibodies, such as antibodies against Sm, double-stranded DNA, SSA/Ro52, nucleosomes, or histones, with diminished levels of the serum complement components, C3 and C4 (Figure. 2A). Three (30.0%) patients (P4, P7, P8) had renal involvement, including proteinuria and gross hematuria, together with massive proteinuria and renal failure, and microscopic hematuria, respectively; among these, P7 underwent kidney biopsy for proliferative sclerosing glomerulonephritis. Three patients with APDS1 (P2, P3, P6) presented with autoimmune thyroiditis, juvenile arthritis, and autoimmune hepatitis, respectively, while autoimmune organ involvement was absent in patients with APDS-L.\u003c/p\u003e \u003cp\u003eFive (50.0%) patients with APDS1 and three (33.3%) with APDS-L had a history of food allergies (Figure. 2A). Five (50.0%) patients with APDS1, one with APDS2, and three (33.3%) with APDS-L were diagnosed with asthma, while three (30.0%) patients with APDS1 presented with chronic eczema, and one (10.0%) patient with APDS1 and one (11.1%) with APDS-L had atopic dermatitis.\u003c/p\u003e \u003cp\u003eFour (40.0%) patients with APDS1 and one with APDS2 had enteropathy/chronic diarrhea (Table I), while three (30.0%) patients with APDS1 (P2, P5, P7) were diagnosed with inflammatory bowel disease by endoscopic biopsy (Figure. 2A).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eNeurological, developmental, and other features\u003c/h2\u003e \u003cp\u003eMacrocrania or motor and language development delay were the initial clinical presentations for consultation in all patients with APDS-L, three of whom (P13, P14, P17) were diagnosed with autism, and one (P15) had a history of seizures (Figure. 2B). Mental retardation was also detected in two (20.0%) patients with APDS1 and both with APDS2. A history of failure to thrive was noted in the majority of patients with APDS1 (90.0%) and APDS2 (100.0%), while this feature was reported in only four (44.4%) patients with APDS-L. Other conditions noted included two (P7, P16) patients with remaining patent foramen ovale; two (P2, P11) with rickets; three (P16, P19, P20) with congenital hypothyroidism; one (P11) with a history of recurrent intussusceptions; one (P20) with bilateral squints; one (P5) with bilateral cryptorchidism; one (P15) with bilateral hernias; one (P21) with bilateral hypoplastic kidneys; one (P15) with laryngomalacia; one (P19) with thumb polydactyly; one (P21) with limb length discrepancy and bilateral hip dislocation; and two (P19, P21) with congenital verrucous nevus and hamartomas, such as hemangiomas and lipomas.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eImmunological laboratory characteristics\u003c/h2\u003e \u003cp\u003eBasic immunological laboratory results of the patients at the time of their first evaluation in our hospital are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; these were not evaluated in most (6 of 9) patients with APDS-L. Reduced IgA (60.0%) and increased IgM (70.0%) levels were common in patients with APDS1, while one patient (P4) had reduced IgM levels, and two had normal IgM levels. IgG levels were variable in patients with APDS1, with four (40.0%) having reduced total IgG levels that were too low to be detected, three (30.0%) having normal IgG levels, and three (30.0%) having high IgG levels. Both patients with APDS2 had reduced IgG and IgA levels, and decreased IgM levels. Of the three cases with APDS-L who underwent testing, one (P15) had reduced IgM levels, one (P16) had reduced IgA levels, and one (P21) had elevated IgM levels; significantly decreased IgG levels were not noted.\u003c/p\u003e \u003cp\u003eIn this cohort, six (60.0%) patients with APDS1 developed B cell lymphopenia, and nine (90.0%) with APDS1 had CD4 T cell lymphopenia. An inverted CD4/CD8 ratio was present in 80% of patients with APDS1 and both of those with APDS2.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eA high degree of variability in the clinical features has been observed in patients with APDS,\u003c/p\u003e \u003cp\u003eand numerous cases presenting with a much more complex phenotype, comprising combined immunodeficiency and immune dysregulation, have been reported [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Here, we present a retrospective analysis of the clinical features in patients with APDS from a single-center in south-central mainland China. This is the third cohort of pediatric patients with APDS from mainland China reported [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our center, recurrent upper respiratory tract infections were described in all patients with the three disease subtypes, while sinusitis and pneumonia were more frequent in patients with APDS1 in our cohort compared with previous studies, partly due to lack of immunoglobulin replacement and antibiotic prophylaxis treatment. Episodes of recurrent bacterial sinopulmonary infections requiring hospitalization for intravenous therapy and medical support, which started early in life (\u0026lt;\u0026thinsp;1 year old), were significantly more frequent in the APDS1 and APDS2 groups than in the APDS-L group. Further, the incidence of bronchiectasis demonstrated by CT, which is a key feature of APDS, was 30% among patients with APDS1 before 7 years old but was not detected in the APDS-L group. Consistent with these findings, analysis of a series of patients with PHTS revealed that sinopulmonary infections were not a major clinical feature [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. By comparison, other infections, including pleuritis, empyema, and peritonitis, were also more common in our cohort, while ocular and urinary tract infections were sporadically documented, which might be ignored by physicians in our center [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn accordance with previous reports [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], encapsulated bacteria, including \u003cem\u003eS. pneumoniae\u003c/em\u003e and \u003cem\u003eH. influenzae\u003c/em\u003e, were the most frequent bacterial pathogens isolated from patients in this study, followed by \u003cem\u003eM. pneumoniae\u003c/em\u003e. Invasive bacterial infections were reported in five cases, indicating more complicated and frequent infections in our patients than previously reported. Mycobacterial infection was described in only one patient with APDS1, who developed local granulomas and tuberculosis after BCG vaccine, similar to previous reports [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Fungal pathogens, such as \u003cem\u003eAspergillus\u003c/em\u003e, were detected in a significant proportion of patients with APDS1 and were more frequent in our cohort than previously described [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. History of EBV infection was also relatively common in the APDS1 group but not described in the APDS2 and APDS-L groups.\u003c/p\u003e \u003cp\u003eLymphoproliferative diseases, including lymphadenopathy, hepatomegaly, splenomegaly, and nodular mucosal lymphoid hyperplasia, another emblematic clinical manifestations, were commonplace in the APDS1 and APDS2 groups but were not detected by physical examination or directly discovered on ultrasound examination in patients with APDS-L. This phenomenon is similar to that described in a previously reported series of patients with PHTS, where lymphoid hyperplasia was apparently rare [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In addition to benign lymphoproliferation, patients with APDS are also at increased risk of malignancies, primarily lymphomas [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. One patient with APDS1 progressed to Hodgkin lymphoma associated with persistent EBV infection at 9 years old, consistent with previous reports that history of lymphoma is significantly associated with EBV but not other herpesviruses [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients with APDS are prone to coexistence of various autoimmune and autoinflammatory conditions, including hematologic, rheumatologic, gastrointestinal, and endocrine disorders, such as cytopenia, arthritis, colitis, enteropathy, and thyroiditis, respectively, as well as dermatologic disorders, which were more frequent in the APDS1 group in our cohort. Autoimmune hemolytic anemia were the most frequent autoimmune complications. Allergic diseases, including asthma, eczema, and food allergy, were also prevalent, as mentioned in other cohorts [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Glomerulosclerosis was detected in one patient with APDS-1, with SLE-like manifestations, which is an atypical pathological presentation of lupus nephritis, consistent with other reports [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Proteinuria, which dominates renal involvement in patients with APDS [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], appears to be related to a mechanism whereby hyperactivated PI3K-Akt signaling in kidney podocytes sensitizes them to injury and apoptosis through endoplasmic reticulum stress [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients with APDS have a variable incidence of neurological and developmental disorders [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In our cohort, neurodevelopmental delay and/or macrocrania were prominent features in the APDS-L group and were the primary abnormalities, attracting considerable attention. A large burden of neurological diseases, including seizures, motor and language development delay, mental retardation, and autism, was present. The high frequency of neurological and developmental involvement is likely due to high PI3K levels in the central nervous system and crosstalk between nervous and immune systems [\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe immunological phenotype hallmarks in patients initially diagnosed with APDS include lymphopenia, reduced B cell count, inverted CD4/CD8 ratio, CD8 T cell senescence, and variable hypogammaglobulinemia [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. CD4 T cell lymphopenia and inverted CD4/CD8 ratio was the most common situation in the APDS1 group, followed by B cell lymphopenia, which is somewhat different from other reports. Low IgA and increased IgM serum levels were prevalent in the APDS1 and APDS2 groups, serum IgG levels were undetectable in APDS2 while broadly normal or elevated in APDS1, notably those presenting with complex complications such as autoimmune disorders. It is noteworthy that these superficial immune function evaluations were frequently not conducted in patients with APDS-L in our cohort.\u003c/p\u003e \u003cp\u003eNo treatment guidelines for APDS are yet available, and management is principally implemented by addressing clinical symptoms, complications, and medical conditions. Several therapeutic modalities have been employed, including conventional immunodeficiency therapies, such as immunoglobulin replacement, antibiotic prophylaxis, and immunosuppression, as well as more targeted therapies, such as mTOR inhibition with sirolimus and selective PI3Kδ inhibitors, or hematopoietic stem cell transplant [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]; however, in general, mortality and complication rates were high in our cohort, predominantly due to diagnostic delay and lack of standard procedures for diagnosis and treatment. Hence, there is an urgent need for consensus and guideline statements.\u003c/p\u003e \u003cp\u003eWe describes clinical phenotypes and disease outcomes of a large cohort of pediatric APDS patients from a single-center in developing countries, and further evaluates differences between subtypes. This study has some obvious limitations. Specifically, it was a retrospective observational study conducted at a single center; the number of included pediatric patients was small, particularly in the APDS2 group; and follow-up time was relatively short, all of which inherently limit analytical power. Furthermore, owing to lack of recognition, the medical records often lacked detailed and comprehensive investigations. Additionally, due to the limitations of laboratory conditions, extensive analyses of immunological characteristics and functions were lacking.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our review indicates highly heterogeneous clinical features among patients with APDS, with those in the ADPS1 and APDS2 groups presenting with more severe immunodeficiency and a higher frequency of developmental delay than patients with APDS-L, while other phenotypes, particularly macrocrania and motor and language development delay, were more frequent in patients with APDS-L.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAPDS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eactivated phosphoinositide 3\u0026ndash;kinase d syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAPDS1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eactivated phosphoinositide 3\u0026ndash;kinase d syndrome caused by mutations in PIK3CD\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAPDS2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eactivated phosphoinositide 3\u0026ndash;kinase d syndrome caused by mutations in PIK3R1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAPDS-L\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eactivated phosphoinositide 3\u0026ndash;kinase d syndrome-like caused by mutations in PTEN\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBALF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebronchoalveolar lavage fluid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBCG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBacillus Calmette-Gu\u0026eacute;rin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEBV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEpstein Barr Virus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGOF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egain-of-function\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLOF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eloss-of-function\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePI3K\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ephosphatidylinositol 3-kinase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePI3Kδ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePI3Kδ Phosphoinositide 3-kinase delta\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePTEN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ephosphatase and tensin homolog\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSLE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esystemic lupus erythematosus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed after obtaining written informed consent from the patients\u0026rsquo; guardians, consistent with the Declaration of Helsinki. This study was approved by the Medical Ethics Committee of Hunan Children\u0026rsquo;s Hospital. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from the patients and their parents.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all participants\u0026nbsp;for the publication of any potentially identifable images or data included in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that all data supporting the findings of this study are available within the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLZ and ZJK designed the study, performed clinical investigations, collected the data, and wrote the manuscript. All authors reviewed the manuscript prior to submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Clinical Medical Technology Innovation and Guidance Project Hunan Province (grant number: 2021SK50502),\u0026nbsp;by the\u0026nbsp;Specialized Diseases Cohort Study\u0026nbsp;Program of Hunan Children\u0026rsquo;s Hospital (grant number: 2021ZBDL03),\u0026nbsp;and by the special fund of the Hunan provincial key laboratory of pediatric orthopedics (grant number: 2023TP1019).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to the patients for their continuous co-operation in this study. We thank the doctors and nurses for their generous support for this project.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B. 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A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome. Blood. 2023;141(9):971\u0026ndash;83. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood.2022018546\u003c/span\u003e\u003cspan address=\"10.1182/blood.2022018546\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Phosphatidylinositol 3-Kinases, PIK3CD, PIK3R1, PTEN, Activated PI3K-delta Syndrome, Primary immune deficiency","lastPublishedDoi":"10.21203/rs.3.rs-3972529/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3972529/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eActivated phosphoinositide 3-kinase delta syndrome causes recurrent respiratory tract infections, lymphoproliferation, autoimmunity, and lymphoma, due to mutations in PI3Kδ subunits, encoded by \u003cem\u003ePIK3CD\u003c/em\u003e and \u003cem\u003ePIK3R1\u003c/em\u003e, or \u003cem\u003ePTEN\u003c/em\u003e, resulting in APDS1, APDS2, and APDS-L subtypes, respectively. Over 400 cases of APDS have been recognized since 2013; however, reports of pediatric patients from China are relatively limited.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eHerein, individuals diagnosed with APDS by whole-exome sequencing from a single center in China were retrospectively assessed. Demographic characteristics, disease complications, laboratory data, and genetics were reviewed based on medical records.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTen, two, and nine patients with APDS1, APDS2, and APDS-L, respectively, were included. All patients with APDS1 had the c.3061G\u0026thinsp;\u0026gt;\u0026thinsp;A mutation in \u003cem\u003ePIK3CD\u003c/em\u003e; patients with APDS2 had heterozygous c.1425\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;C and c.1425\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A mutations in \u003cem\u003ePIK3R1\u003c/em\u003e; and of patients with APDS-L, four had c.388C\u0026thinsp;\u0026gt;\u0026thinsp;T, and the other five had c.697C\u0026thinsp;\u0026gt;\u0026thinsp;T, c.1031delA, c.202T\u0026thinsp;\u0026gt;\u0026thinsp;C, c.640C\u0026thinsp;\u0026gt;\u0026thinsp;T, and c.896dupA mutations in \u003cem\u003ePTEN\u003c/em\u003e. Recurrent respiratory tract infections were the most common manifestations in all patients. Neurodevelopmental abnormalities were noted in all patients with APDS-L. Bronchiectasis, chronic lymphoproliferation, and autoimmunity were more common in patients with APDS1 and APDS2. Five patients with APDS1 died from complications, including severe bacterial infection, autoimmune disease, renal failure, and lymphoma. Decreased serum IgG levels, increased IgM levels, B cell lymphopenia, and CD4 lymphopenia were predominant immunologic features in patients with APDS1 and APDS2.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAPDS is a combined immunodeficiency with variable clinical manifestations. Patients with APDS1 and APDS2 had more frequent and severe infections than those with APDS-L. Neurodevelopmental delay was common in patients with APDS-L. APDS can be fatal; appropriate management is required to improved patient outcomes.\u003c/p\u003e","manuscriptTitle":"Multiple presentations of pediatric activated PI3K-delta syndrome: a single-center experience in south-central mainland China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-06 19:36:15","doi":"10.21203/rs.3.rs-3972529/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2024-03-03T22:48:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-22T06:01:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"Italian Journal of Pediatrics","date":"2024-02-19T08:15:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5db76122-4258-4ecb-9460-3fdc87551f81","owner":[],"postedDate":"March 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-03-06T19:36:16+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-06 19:36:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3972529","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3972529","identity":"rs-3972529","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}