32-year-old male, son of the index case

Patient Characteristics

A 27-month-old girl was referred due to recurrent fever, arthritis, and erythema nodosum to the rheumatology clinic of Mofid Children’s Hospital (Tehran, Iran). She was the second alive child of consanguineous marriage (G2P2L2) with a 3800-gram birth weight and a history of neurodevelopmental delays in walking (at the age of 21 months) and speaking (at the age of 24 months). There is no positive point in the family history, except for the mother, who had hypothyroidism and a history of frequent respiratory infections in childhood.She had a history of several hospital admissions after her birth. First, she was admitted at two months old with a fever and high levels of ESR and CRP. She received antibiotics for five days and was discharged with no signs or symptoms but still had high ESR and CRP.At 8 months old, she was evaluated due to failure to thrive (FTT). During patient examinations, the low heart rate, muffled heart sound, and massive pericardial effusion were found in her echocardiography. The pericardial effusion caused her to be hospitalized for 16 days in the intensive care unit (ICU). Pericardial effusion was tapped without any infectious resources. Pericardial effusion was treated with prednisolone, and she was discharged in good condition. Two months later, she was hospitalized again with recurrent pericardial effusion for 19 days. In evaluations, she had hypothyroidism and a little pericardial effusion. She was treated with dexamethasone, ibuprofen, and levothyroxine.Fourth and fifth hospitalizations occurred due to high-grade fever and elevated ESR and CRP levels at the 13th and 18th months of old, respectively.She got COVID-19 at 24 months old and was admitted to the hospital for the 6th time because of her past medical history. She had only a fever as a COVID-19 manifestation. After 4 months, she got COVID-19 again and had gastrointestinal manifestations without any adverse effects.At the age of 27 months, the patient was referred to the rheumatology clinic due to several episodes of high grade fever, inflammatory pericardial effusion, and active left knee arthritis with an increase in inflammatory marker levels without any localized origin, as well as an erythematous plaque on the leg and a history of multiple hospitalizations. A skin biopsy revealed septal panniculitis compatible with erythema nodosum. The patient was thoroughly evaluated in terms of rheumatology, her height, and weight were 82 cm and 10 kg in physical examination, respectively. We found blonde hair, frontal bossing, and macular rashes on limbs, and eventually, according to the lack of response to treatment and the history of respiratory infections, an immunological examination including CBC, CD markers, and immunoglobulins levels was performed. The clinical manifestations of the patient are shown in Fig. 1.Open in a separate windowFig. 1The clinical manifestation of the patient Low serum IgG levels, decreased CD4/CD8 ratio and CD27 level, and a poor response to candida in the lymphocyte transformation test (LTT) were detected (Table 1). Intravenous immunoglobulin (IVIG) and prophylactic antibiotics were started which led to the control of the patient’s fever and other symptoms.Table 1The results of hematological, biochemical and immunological tests of the patientTestValueNormal RangeTestValueNormal Range WBC(cell/mm 3 ) 89006000–17,000 IgM ( mg/dl) 5940–150 Neutrophil(cell/mm 3 ) 44501500–8500 IgG( mg/dl) 520600–1100 Lymphocyte(cell/mm 3 ) 36043000–9500 IgA ( mg/dl) 2151–297 Hb(g/dl) 7.411.5–13.5 IgE ( IU/ml) 1Up to 144 PLT 566,000150,000–450,000 CD3%(total count) 65.2 (3338)35–78% ANA NegativeNL < 1/160 CD4%(total count) 33 (1690)22–62% RF NegativeNeg < 10 CD8%(total count) 32.3 (1654)12–36% Anti Ds DNA NegativeNeg < 2.6 CD19%(total count) 11 (563)3–14% HLAB51 Negative CD20%(total count) 13.2 (676)3–15% Anti CCP NegativeNeg < 0.3 CD16%(total count) 15.4 (229)3–5% Anti Phospholipid Ab NegativeNegative CD56%(total count) 16.23–5%Anti SSA(RO)NegativeNeg < 15 CD4/CD8 1.021.5-2Anti SSB(La)NegativeNeg < 20 CD27% 3.909–35% ESR (mm/hr) 57 (H)Nl < 20 LTT(PHA) 7.1Nl˃3.5 CRP (mg/L) 43Nl < 6 LTT (Candida) 1.5Nl˃2.5Anti-Tetanus Ab(IU/ml)1.57˃0.1LTT (BCG)6.2Nl˃2.5Anti-Diphtheria Ab(IU/ml)0.29˃0.01Open in a separate windowWBC: White Blood cell, Hb: Hemoglobin, PLT: Platelet, ANA: AntiNuclear Antibody, RF: Rheumatoid Factor, Anti Ds DNA: Anti Double stranded DNA, Anti CCP: Anti Cyclic Citrullinated Peptide, Anti SSA Ab: anti–Sjögren’s-syndrome-related antigen A autoantibody, Anti SSB: anti–Sjögren’s-syndrome-related antigen B autoantibody, ESR: Erythrocyte Sedimentation Rate, CRP: C-reactive Protein, Ig: Immunoglobulin, LTT: lymphocyte transformation test, PHA: Phytohemagglutinin, BCG: Bacillus Calmette-Guerin After about 5 months of the follow-up, the patient was hospitalized due to polyuria, polydipsia, tachypnea, and lethargy with the diagnosis of diabetic ketoacidosis and was discharged with injectable insulin. Whole-exome sequencing was performed on the patient’s whole blood sample. Variant interpretation of interested variants was accomplished through the American College of Medical Genetics and Genomics (ACMG). A novel heterozygous variant (c.1429 G > A; p.Glu477Lys) was found in the PIK3CD gene (Table 2). The variant was validated in the patient, and segregation analysis showed the mother is the carrier for the variant. According to the ACMG guideline, this variant can be classified as a Variant of Unknown Significance (VUS).Table 2The result of genetic sequencing of the patientGene/TranscriptVariant LocationChromosome position(GRCh37)Relationship with the patientZygosityVariant classificationPIK3CDENST00000377346.4NM-005026Exon11c.1429G > Ap.E477KProbandHetVUSMotherHetFatherN

We conducted WGS on a 20-year-old Spanish proband (only child), who exhibited classical symptoms of IDAIL, including early-onset type 1 diabetes (diagnosed at 15 months old), severe enteritis, genital vitiligo and atopic dermatitis. Throughout his childhood, he faced recurrent respiratory infections, including pneumonia, alongside pronounced reactive hypereosinophilia, which constituted up to approximately 65% of total peripheral blood mononuclear cells (PBMCs) at times. Notably, at the age 13, he experienced severe diarrhea and ascites, accompanied by eosinophil infiltration in the esophagus, stomach, and bone marrow. Medical investigations revealed a clonal γδ T cell band, characterized as reactive, with subsequent exclusion of FIP1L1-PDGFRA and PDGFRB rearrangements, as well as any abnormal karyotype. Over time, he developed esophageal candidiasis and sepsis due to Salmonella typhi and Clostridium difficile infection, which was accompanied by a gradual development of hypogammaglobulinemia. A complete clinical case description is included in the Supplementary Materials.Bioinformatic analysis revealed a known pathogenic maternally inherited missense variant in CTLA4, c.208C>T p.R70W, confirmed by Sanger sequencing (Fig. 1, A to D). This heterozygous variant has been previously reported to be causative of CTLA4-h with incomplete penetrance (1, 2). The R70W variant was also present in the patient’s mother who had been diagnosed with mild sarcoidosis, dysphagia with eosinophilic infiltrates of esophagus, low IgM, and decreased percentages of memory B cells.