A novel tissue‐based ß‐catenin gene and immunohistochemical analysis to exclude familial adenomatous polyposis among children with hepatoblastoma tumors

1 Background

The Wnt/β‐catenin pathway plays a central role in the pathogenesis of most hepatoblastomas (HBs), that is, up to 60–80% carry activating CTNNB1 mutations. HBs can however also be the first manifestation of familial adenomatous polyposis (FAP). As this is a severe disease, it is important for the patient and related family members to firmly exclude FAP at an early stage. Current diagnosis largely depends on APC germline mutation detection on genomic DNA, which is associated with 10–20% false‐negative results. Here, we establish and validate a tissue‐based β‐catenin gene and immunohistochemical analysis, which complements germline mutation screening to exclude the diagnosis of FAP among HB patients.

2 Methods

Tumor tissues of 18 HB patients, including three FAP cases were subjected to CTNNB1 exon 3 mutational analysis and immunohistochemistry comparing staining patterns for total and exon 3 specific β‐catenin antibodies.

3 Results

Our novel tissue‐based method reliably identified all three FAP patients. Their tumors were characterized by a wild‐type exon 3 sequence and a comparable nuclear staining for both antibodies. In contrast, the non‐FAP tumors carried missense CTNNB1 mutations combined with a clearly reduced staining for the exon 3 antibody, or complete loss of staining in case of lesions with exon 3 deletions.

4 Conclusion

We have successfully established and validated a novel ß‐catenin gene and immunohistochemical diagnostic method, which, when combined with routine germline DNA testing, allows the exclusion of the diagnosis of FAP among HB patients.     

Desmoid‐type fibromatosis in a boy with Down syndrome

Patients with Down syndrome (DS) have a markedly higher incidence of childhood leukemia, but a lower incidence of most solid tumors, compared with age‐matched euploid individuals. Trisomy 21 might be protective against tumorigenesis because of several tumor suppressive mechanisms. Desmoid‐type fibromatosis (DF) is a rare monoclonal, fibroblastic proliferation characterized by a variable clinical course. In recent reports, almost all cases of DF involved genomic alterations associated with activation of the Wnt/β‐catenin pathway. Here, we report the case of a boy with DS who developed DF without activation of the Wnt/β‐catenin pathway. To the best of our knowledge, this is the first case of DS involving DF.     

Role of Wnt inhibitory factor‐1 and Wnt/wingless signaling in choroid plexus tumors

Little is known on pathways involved in the pathogenesis of choroid plexus tumors (CPTs). The finding of overexpression of Wnt inhibitory factor‐1 (Wif‐1) prompted us to investigate the functional role of Wif‐1 as well as nuclear accumulation of beta‐catenin in CPT. In Z310 neoplastic choroid plexus epithelial cells, silencing of Wif1 expression increased proliferative activity not associated with increased canonical Wnt signaling. Nuclear beta‐catenin accumulation was also lacking in a series of 16 CPT. In conclusion, our data show that Wif‐1 inhibits proliferation of neoplastic choroid plexus epithelial cells, but argue against a role of canonical Wnt/wingless signaling in CPT. Pediatr Blood Cancer 2009;53:1152–1155. © 2009 Wiley‐Liss, Inc.     

Effect of recombinant human fibroblast growth factor‐2 on bone formation in rabbit mandibular distraction models using β‐tricalcium phosphate

This study was designed to evaluate the effect of recombinant human fibroblast growth factor‐2 (rhFGF‐2) on the amount and period of new bone formation in rabbit mandibular distraction models using β‐tricalcium phosphate (β‐TCP) as a bone graft substitute. Sixteen male Japanese White rabbits were divided into the following four experimental groups: 1, distraction alone; 2, distraction with β‐TCP granules; 3, distraction with rhFGF‐2 (25 µg/50 µL) injected into β‐TCP granules; and 4, distraction with rhFGF‐2 (100 µg/50 µL) injected into β‐TCP granules. The bones were harvested at 4 weeks after the operation and examined using soft radiography, micro‐computed tomography (micro‐CT), and peripheral quantitative computed tomography (pQCT). The dissected mandibles were stained using the Villanueva bone staining method, and the amount of new bone formed, bioresorption of β‐TCP, and new blood vessel formation were morphometrically calculated using bone histomorphometry. Radiopaque areas were observed more frequently in the distracted area of groups 3 and 4. Micro‐CT analysis revealed partial new bone formation in the central region of the distracted area in groups 3 and 4. pQCT analysis revealed increased bone mineral density in groups 3 and 4. Histomorphometric analysis revealed increased newly formed bone and blood vessel areas in groups 3 and 4. In group 4, the number of osteoclasts around the β‐TCP granules had significantly increased. The present findings suggested that the combined use of rhFGF‐2 and β‐TCP reduced the treatment period for distraction osteogenesis and accelerated the formation of a new high‐quality bone.     

Prevalence of low bone mass among adolescents with nontransfusion‐dependent hemoglobin E/β‐thalassemia and its relationship with anemia severity

1 Background

Low bone mass is common among adolescents with transfusion‐dependent β‐thalassemia despite adequate transfusion and iron chelation. However, there are few reports regarding bone mineral density (BMD) among adolescents with nontransfusion‐dependent thalassemia (NTDT). Indeed, only BMD data in patients with nontransfusion‐dependent (NTD) β‐thalassemia intermedia have been reported. No previous study has investigated BMD among adolescents with NTD hemoglobin (Hb) E/β‐thalassemia.

2 Objective

To determine the prevalence of low bone mass among adolescents with NTD Hb E/β‐thalassemia and factors relating to low bone mass.

3 Methods

We investigated BMD of lumbar spine (L2–L4; BMDLS) and total body (BMDTB), as measured by dual‐energy X‐ray absorptiometry, in 22 adolescents (aged 13.2–20 years) with NTD Hb E/β‐thalassemia.

4 Results

Low bone mass was found to be 18.2% and 22.7% at the lumbar spine (BMDLS Z‐score adjusted for bone age and height age) and 13.6% and 9.1% at the total body (BMDTB Z‐score adjusted for bone age and height age). Patients with mean Hb level <8 g/dl were more likely to have low bone mass (BMDLS and BMDTB Z‐scores adjusted for bone age) compared to those with Hb level ≥ 8 g/dl. Mean Hb level correlated with BMDLS and BMDTB Z‐scores adjusted for bone age.

5 Conclusion

We demonstrated that a low Hb level was associated with low bone mass among adolescents with NTD Hb E/β‐thalassemia. A significant proportion of low bone mass among these patients highlights the importance of appropriate management, including red cell transfusion, vitamin D and calcium supplementation for improved long‐term bone health.     

Impaired β‐cell sensitivity to glucose and maximal insulin secretory capacity in adolescents with type 2 diabetes

Elder DA, Woo JG, D’Alessio DA. Impaired β‐cell sensitivity to glucose and maximal insulin secretory capacity in adolescents with type 2 diabetes. Background: Adults with type 2 diabetes mellitus (T2DM) have broad impairments in β‐cell function, including severe attenuation of the first‐phase insulin response to glucose, and reduced β‐cell mass. In adolescents with T2DM, there is some evidence that β‐cell dysfunction may be less severe. Our objective was to determine β‐cell sensitivity to glucose and maximal insulin secretory capacity (AIR_max) in teenagers with T2DM. Methods: Fifteen adolescents with T2DM [11 F/4 M, age 18.4 ± 0.3 yr, body mass index (BMI) 39.8 ± 2.2 kg/m²] and 10 non‐diabetic control subjects (7 F/3 M, age 17.4 ± 0.5 yr, BMI 41.5 ± 2.2 kg/m²) were studied. T2DM subjects had a mean duration of diabetes of 48.8 ± 6.4 months, were treated with conventional therapies, and had good metabolic control [hemoglobin A1c (HbA1c) 6.7 ± 1.2%]. Insulin and C‐peptide were determined before and after a graded glucose infusion and after intravenous arginine at a whole blood glucose level of ≥22 mM. Results: The insulin response to increasing plasma glucose concentrations was blunted in the diabetic compared with control subjects (34.8 ± 11.9 vs. 280.5 ± 57.8 pmol/mmol; p < 0.0001), and AIR_max was also significantly reduced in the diabetic group (1868 ± 330 vs. 4445 ± 606; p = 0.0005). Conclusion: Even adolescents with well‐controlled T2DM have severe impairments of insulin secretion. These data support β‐cell dysfunction as central in the pathogenesis of T2DM in young people, and indicate that these abnormalities can develop over a period of just several years.     

Neurocognitive function in patients with β‐thalassemia major

Background: Children with β‐thalassemia major (β‐TM) have multiple risk factors for developing cognitive impairment. The aim of the present study was to evaluate cognitive function in patients with β‐TM. Methods: Twenty children with β‐TM were enrolled into the study and were compared with a control group consisting of 21 healthy children. All participants were evaluated with neuropsychological tests and event‐related potentials (ERP). Results: All of the participants had normal IQ scores, but the patient group had significantly lower full‐scale, performance, and verbal IQs compared with the control group (P < 0.05). The number of children with visuomotor dysfunction was higher in the patient group compared with the control group (P < 0.05). In the P300 test, the patient group had significantly prolonged N1, P2 and N2 latencies at the FZ, and a prolonged N1 latency at the Cz compared with the control group (P < 0.05). The patient group also had lower N1 and P3N4 amplitudes at the Fz, and lower N1, N1P2 and P3N4 amplitudes at the Cz when compared with the control group (P < 0.05). Mismatch negativity latency and duration were longer in the patient group (P < 0.05). Conclusions: Neuropsychological tests are safe, and reliable for the diagnosis of cognitive impairment in β‐TM patients, and the use of ERP may facilitate early diagnosis. The number of β‐TM patients in the present study was limited, however, and larger numbers of patients are required in further studies.     

Prostaglandin E‐mediated molecular mechanisms driving remodeling of the ductus arteriosus

The ductus arteriosus (DA), a fetal arterial connection between the pulmonary arteries and aorta, normally closes after birth. Persistent DA patency usually has life‐threatening consequences. In certain DA‐dependent congenital heart diseases, however, patient survival depends on maintaining DA patency. Complete closure of the DA involves both functional closure, induced by muscle contraction, and anatomical closure, achieved through morphological and molecular remodeling. Anatomical closure of the DA is associated with the formation of intimal thickening, which is characterized by deposition of extracellular matrix in the subendothelial region, sparse elastic fiber formation, and migration of medial smooth muscle cells into the subendothelial space. In addition, fetal molecular remodeling that is suitable for postnatal muscle contraction has been observed in the DA. After the second trimester, high concentration of prostaglandin E₂ (PGE₂) causes the DA to dilate through the remainder of the fetal period. Emerging evidence from studies using pharmacological approaches and genetically modified mice suggests that, in addition to its vasodilatory effect, this chronic exposure to PGE₂ promotes DA‐specific anatomical and molecular remodeling through EP4, one of four receptor subtypes for PGE₂. Signals that are downstream of PGE₂‐EP4, such as cyclic AMP (cAMP)‐protein kinase A (PKA), exchange protein activated by cAMP (Epac), phospholipase C, and Wnt/β‐catenin, may be involved in the regulation of intimal thickening, elastogenesis, and contraction‐related genes. Understanding the physiological role of PGE₂ in DA remodeling could enable more effective regulation of PDA, both in isolation and in the context of congenital cardiac anomalies.     

Culture conditions for the detection of allergen‐specific T‐cell reactivity in cord blood: Influence of cell number

Raised T‐cell proliferation of cord blood mononuclear cells (CBMC) in response to various ingestant and inhalant allergens has been reported in newborns, suggesting a prenatal allergen contact. In general, for in vitro proliferation assays a concentration of 50 × 10³ or 100 × 10³ cells/well are used. The aim of this study was to analyze whether cell concentration influences T‐cell reactivity in cord blood cells and to study differences of T‐cell reactivity triggered by inhalant and ingestant allergens. CBMC from 51 neonates (34 females: 22 with and 29 without a family history of allergy, i.e. FH+ or FH–) were incubated with interleukin‐2 (IL‐2), β‐lactoglobulin (β‐LG), ovalbumin (OVA), house dust mite allergen Dermatophagoides pteronyssinus (Der p 1), and timothy grass allergen Phleum pratense (Phl p 1) for 7 days. The cell concentration ranged from 62.5 × 10³ to 100 × 10³ cells/well. Proliferation was assessed by incorporation of [³H]‐thymidine and was expressed as counts per minute (c.p.m.). In unstimulated cells, a decreasing cell concentration paralleled a steep drop of background activity. In response to IL‐2, a decreasing cell concentration led to a slow decrease of c.p.m. The corresponding mean stimulation indices (SI) were 9, 32, 77, 47, and 21 for 100 × 10³, 50 × 10³, 25 × 10³, 12.5 × 10³, and 62.5 × 10³ cells/well, respectively. In addition, the highest number of positive proliferative responses to specific allergens were obscured at lower cell concentrations. For β‐LG, the maximal number of positive responses were obtained between 25 × 10³ (n = 44) and 12.5 × 10³ (n = 46) cells/well, for OVA at 25 × 10³ (n = 3) cells/well, for Der p 1 at 50 × 10³ (n = 5) cells/well, and for Phl p 1 between 25 × 10³ and 12.5 × 10³ (n = 5) cells/well. Positive proliferation in at least one of the tested assays was observed in 100% of samples in response to β‐LG, in 22% in response to Phl p 1, and in 14% in response to OVA and Der p 1. T‐cell reactivity did not differ between samples of newborns with or without a family history of atopy. Therefore, sensitivity of T‐cell proliferation measurement is highly influenced by background proliferation of unstimulated cells. Hence, proliferation assays with lower cell numbers unmask T‐cell reactivity in response to ingestant and inhalant allergens. We suggest the use of concentrations of 12.5 × 10³–50 × 10³ cells/well in proliferation experiments.     

Trends in the off‐label use of β‐blockers in pediatric patients

The use of US Food and Drug Administration (FDA)‐approved drugs for the treatment of an unapproved indication or in an unapproved age group, or at doses or route of administration not indicated on the label is known as off‐label use. Off‐label use may be beneficial in circumstances when the standard‐of‐care treatment has failed, and/or no other FDA‐approved medications are available for a particular condition. In pediatric patients, off‐label use may increase the risk of adverse events as pharmacokinetic and pharmacodynamic data are limited in children. Approximately 73% of off‐label drugs currently prescribed for various conditions do not have sufficient scientific evidence for safety and efficacy. For example, β‐blockers are a class of drugs with FDA‐approval for very few indications in pediatrics but are commonly used for various off‐label indications. Interestingly, the proportion of off‐label use of β‐blockers in adults is at about 52% (66.2 million) of the total number of β‐blockers prescribed. The frequency of off‐label use of β‐blockers in children is also high with limited data on the indications as well as safety and efficacy. We present trends in off‐label use of β‐blockers in children to discuss drug safety and efficacy and include recommendations for pediatric providers.     

Successful unrelated umbilical cord blood transplantation for class 3 β‐thalassemia major using a reduced‐toxicity regimen

Unrelated umbilical CB transplant for class 3 β‐thalassemia major is associated with an increased risk of mortality and non‐engraftment. We describe two patients who underwent successful unrelated umbilical CB transplant using a novel reduced‐toxicity preparative regimen. This regimen may be sufficiently immunosuppressive and myeloablative to ensure engraftment with reduced risks of toxicity and mortality. Close monitoring of HHV‐6 viral load is advised for patients undergoing transplant with this regimen.     

Refractory cardiogenic shock in a patient with β‐thalassemia major requiring mechanical circulatory support: Case report and literature review

Iron overload cardiomyopathy secondary to β‐thalassemia major is a potentially reversible condition managed with chelation and medical hemodynamic support, as bridge‐to‐recovery or transplant. We describe our experience, and challenges faced, in a pediatric patient with iron overload cardiomyopathy secondary to β‐thalassemia major, requiring biventricular MCS.     

Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, and X‐linked (IPEX) syndrome is an autoimmune disorder caused by the dysfunction of FOXP3, which leads to regulatory T‐(Treg) cell dysfunction and subsequently autoimmunity including type 1 diabetes mellitus (T1D). Presently, allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative therapy for IPEX syndrome, but not for T1D. Generally, after complete loss of pancreatic β‐cells, HSCT cannot improve the prognosis of T1D. Here, we report the case of a 16‐year‐old adolescent with late‐onset of FOXP3 R347H mutation associated IPEX syndrome with T1D, where insulin dependency was ameliorated following HSCT. This patient with insulin‐dependent diabetes mellitus required insulin dosage of 1.28 U/kg/day for 1 month before HSCT. Although the results of glucose homeostasis before HSCT revealed impaired insulin secretion and low ΔC‐peptide immunoreactivity (CPR, 1.0 ng/mL), the patient withdrew insulin infusion and remained euglycemic at 15 months after HSCT, and had normal β‐cell function with improved ΔCPR (3.4 ng/mL) at 20 months after HSCT. The present case suggests that HSCT for T1D‐associated IPEX syndrome improves Treg deficiency and prevents elimination of β‐cells. We speculate that the period from the onset of T1D to HSCT could affect the therapeutic efficacy for T1D with IPEX, and early intervention with HSCT before or immediately after the onset of DM can rescue β‐cells and remit T1D completely. Our study elaborates not only the therapeutic strategy for T1D with IPEX, but also the pathogenic mechanism in general T1D.     

Up-regulation of fetal rat lung parathyroid hormone-related protein gene regulatory network down-regulates the Sonic Hedgehog/Wnt/betacatenin gene regulatory network

Lung development depends on endodermal Sonic Hedgehog (Shh) signaling to mesodermal Wingless/int/beta catenin (Wnt/betacatenin), followed by parathyroid hormone-related protein (PTHrP) signaling from endoderm to mesoderm. Fluid distension of fetal rat lung explants up-regulates PTHrP signaling and down-regulates Shh/Wnt/betacatenin signaling, marked by decreases in Patched, Gli, Frizzled, and Dishevelled, inducing fibroblast triglyceride uptake, type II cell saturated phosphatidylcholine, and surfactant protein-B expression. Bumetanide, which inhibits fluid distension, blocked down-regulation of the Shh/Wnt/betacatenin pathway and up-regulation of the PTHrP pathway, whereas PTHrP (1-34, 5 x 10(-7) M) treatment overcame bumetanide inhibition, and the PTHrP receptor antagonist PTHrP (7-34) amide (5 x 10(-6) M) mimicked bumetanide, indicating that PTHrP signaling mediates fluid distension-induced alveolar differentiation. Fetal rat lung explant automaturation was characterized by decreased Wnt/betacatenin signaling and increased PTHrP/PTHrP receptor signaling, up-regulating fibroblast-specific adipocyte differentiation related protein (ADRP) and peroxisome proliferator-activated receptor gamma. Wnt/betacatenin agonists (LiCl or SB415268) maintained Shh/Wnt/betacatenin signaling, blocking spontaneous up-regulation of the PTHrP pathway, whereas PTHrP or cAMP down-regulated Shh/Wnt/betacatenin signaling and stimulated PTHrP signaling for fibroblast and type II cell differentiation. This is the first evidence that alveolar fluid distension is an organizing principle for PTHrP signaling down-regulation of the Shh/Wnt/betacatenin pathway.     

Bmp4 is an essential growth factor for the initiation of genital tubercle (GT) outgrowth

The external genitalia are appendage organs outgrowing from the posterior body trunk. Murine genital tubercle (GT), anlage of external genitalia, initiates its outgrowth from embryonic day (E) 10.5 as a bud structure. Several growth factors such as fibroblast growth factor (FGF), Wnt and Sonic hedgehog (Shh) are essential for the GT outgrowth. However, the mechanisms of initiation of GT outgrowth are poorly understood. We previously identified bone morphogenetic protein (Bmp) signaling as a negative regulator for GT outgrowth. We show here novel aspects of Bmp4 functions for GT outgrowth. We identified the Bmp4 was already expressed in cloaca region at E9.5, before GT outgrowth. To analyze the function of Bmp4 at early stage for the initiation of GT outgrowth, we utilized the Hoxa3-Cre driver and Bmp4 ^flox/flox mouse lines. Hoxa3 ^Cre/+; Bmp4 ^flox/flox mutant mice showed the hypoplasia of GT with reduced expression of outgrowth promoting genes such as Wnt5a, Hoxd13 and p63, whereas Shh expression was not affected. Formation of distal urethral epithelium (DUE) marked by the Fgf8 expression is essential for controlling mesenchymal genes expression in GT and subsequent its outgrowth. Furthermore, Fgf8 expression was dramatically reduced in such mutant mice indicating the defective DUE formation. Hence, current results indicate that Bmp4 is an essential growth factor for the initiation of GT outgrowth independent of Shh signaling. Thus, Bmp4 positively regulates for the formation of DUE. The current study provides new insights into the function of Bmp signaling at early stage for the initiation of GT outgrowth.     

Differences in β‐cell function and insulin secretion in Black vs. White obese adolescents: do incretin hormones play a role?

Black youth are at higher risk for type 2 diabetes (T2D) than their White peers. Previously we demonstrated that for the same degree of insulin sensitivity, Black youth have an upregulated β‐cell function and insulin hypersecretion, in response to intravenous (iv) glucose, compared with Whites. To investigate if the same holds true during an oral glucose challenge and because of the important role of glucagon‐like peptide 1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) in augmenting insulin secretion, we examined β‐cell function and incretin hormones in 85 Black and 78 White obese adolescents, with normal glucose tolerance (NGT), during a 2‐h oral glucose tolerance test (OGTT) with mathematical modeling of plasma glucose and C‐peptide concentrations to assess β‐cell glucose sensitivity (βCGS), rate sensitivity, potentiation factor, and insulin sensitivity. Incretin, pancreatic polypeptide, and glucagon concentrations were measured during the OGTT. Black obese youth had a heightened early insulin secretion together with significantly greater βCGS, rate sensitivity, and potentiation factor compared with Whites, with no differences in incretin and glucagon concentrations. Basal and stimulated insulin clearance was lower (p = 0.001) in Black vs. White youth. In conclusion, during an OGTT Black obese youth with NGT demonstrate a pronounced early insulin secretion jointly with heightened β‐cell glucose sensitivity, rate sensitivity, and potentiation factor. These racial disparities in β‐cell function and the pathophysiological components of T2D are unlikely to be attributed to incretin hormones and remain to be investigated further to explain the metabolic basis for the enhanced risk of T2D in back youth.     

Polycystic brain (cerebrum polycystica vera) associated with ectodermal dysplasia: A new neurocutaneous syndrome

This paper presents a unique case of true polycystic brain in which multiple cysts of curvilinear, round, oval, or layered configuration occurred. These apparently represented extremely dilated Virchow-Robin spaces: the perivascular spaces lined by ependymal/leptomeningeal cells. Irregular retinal pigment epithelium was also evident. In addition, the patient showed ectodermal dysplasia manifesting as thin hair, dystrophic nails, and dental abnormalities. A common ectodermal origin for the brain cysts and the ectodermal changes is proposed, as it is known that the central nervous system (including the ependymal/leptomeningeal cells and the retinal cells), the epidermis (including hair and nails), and the enamel of the teeth have the same origin — the embryonic ectoderm. This association appears to be a new, distinct neurocutaneous syndrome.     

A case of moyamoya syndrome and hemoglobin E/beta‐thalassemia

Moyamoya syndrome is a rare diagnosis that has been linked to a small number of hemoglobinopathies. Children with Moyamoya syndrome tend to present with transient ischemic attacks, mental deficiency, and/or neurological deficits. We describe a case of a 15‐year‐old Cambodian male with HbE/β‐thalassemia who was found to have left Moyamoya syndrome as part of an evaluation for growth hormone deficiency. The link between Moyamoya syndrome and HbE/β‐thalassemia may be multifactorial, but Moyamoya syndrome is an important consequence to consider in children with HbE/β‐thalassemia. Pediatr Blood Cancer 2009;52:422–424. © 2008 Wiley‐Liss, Inc.     

Subcutaneous immunoglobulin replacement following CD19‐specific chimeric antigen receptor T‐cell therapy for B‐cell acute lymphoblastic leukemia in pediatric patients

Twenty‐eight patients were maintained on subcutaneous immunoglobulin replacement for persistent B‐cell aplasia and agammaglobulinemia following CD19‐targeted chimeric antigen receptor T‐cell therapy for B‐cell lymphoblastic leukemia. Patients were transitioned from intravenous to subcutaneous immunoglobulin replacement at a median of 11.5 months (range, 4‐20). Increasing serum IgG level was significantly associated with a lower rate of sinopulmonary infection (P = 0.0072). The median serum IgG level during infection‐free periods was 1000 mg/dL (range, 720‐1430), which was significantly higher than IgG levels in patients with sinopulmonary infections. As such, we recommend maintaining a goal IgG level > 1000 mg/dL to provide optimal protection.