Language and sensory characteristics are reflected in voice-evoked responses in low birth weight children.

BACKGROUND: Children born with very low birth weight (VLBW) are at higher risk for cognitive impairment, including language deficits and sensorimotor difficulties. Voice-evoked response (P1m), which has been suggested as a language development biomarker in young children, remains unexplored for its efficacy in VLBW children. Furthermore, the relation between P1m and sensory difficulties in VLBW children remains unclear. METHODS: 40 children with VLBW were recruited at 5-to-6 years old (26 male, 14 female, mean age of months ± SD, 80.0 ± 4.9). We measured their voice-evoked brain response using child-customized magnetoencephalography (MEG) and examined the relation between P1m and language conceptual inference ability and sensory characteristics. RESULTS: The final sample comprised 36 children (23 boys, 13 girls; ages 61-86 months; gestational ages 24-36 weeks). As a result of multiple regression analysis, voice-evoked P1m in the left hemisphere was correlated significantly with language ability (ß = 0.414 P = 0.015) and sensory hypersensitivity (ß = 0.471 P = 0.005). CONCLUSION: Our findings indicate that the relation between P1m and language conceptual inference ability observed in term children in earlier studies is replicated in VLBW children, and suggests P1m intensity as a biomarker of sensory sensitivity characteristics. IMPACT: We investigated brain functions related to language development and sensory problems in very low birth-weight children. In very low birth weight children at early school age, brain responses to human voices are associated with language conceptual inference ability and sensory hypersensitivity. These findings promote a physiological understanding of both language development and sensory characteristics in very low birth weight children.

Neural responses to syllable-induced P1m and social impairment in children with autism spectrum disorder and typically developing Peers.

In previous magnetoencephalography (MEG) studies, children with autism spectrum disorder (ASD) have been shown to respond differently to speech stimuli than typically developing (TD) children. Quantitative evaluation of this difference in responsiveness may support early diagnosis and intervention for ASD. The objective of this research is to investigate the relationship between syllable-induced P1m and social impairment in children with ASD and TD children. We analyzed 49 children with ASD aged 40-92 months and age-matched 26 TD children. We evaluated their social impairment by means of the Social Responsiveness Scale (SRS) and their intelligence ability using the Kaufman Assessment Battery for Children (K-ABC). Multiple regression analysis with SRS score as the dependent variable and syllable-induced P1m latency or intensity and intelligence ability as explanatory variables revealed that SRS score was associated with syllable-induced P1m latency in the left hemisphere only in the TD group and not in the ASD group. A second finding was that increased leftward-lateralization of intensity was correlated with higher SRS scores only in the ASD group. These results provide valuable insights but also highlight the intricate nature of neural mechanisms and their relationship with autistic traits.

Relationship between children with neurodevelopmental disorders and their caregivers and friends during early phase of COVID-19 school closure in Japan: Association with difficulty in implementing infection prevention measures.

BACKGROUND: Due to the COVID-19 pandemic people had to implement various infection prevention measures. Researchers have reported the difficulties experienced by children with neurodevelopmental disorders in implementing these measures and their caregivers' resultant anxiety and stress. This study examined the relationship between these difficulties and the deterioration of the children's relationships with their caregivers and friends during school closure and after school reopened. METHODS: A total of 150 caregivers of children with neurodevelopmental disorders answered a questionnaire asking about parent‒child relationships, their child's friendships, and the presence or absence of difficulty in implementing infection prevention measures at three time points: before the pandemic, while schools were closed, and after school reopened. The frequency and percentages of the child's behavioral problems, deterioration in their relationships, and difficulty implementing infection control measures were calculated. Using the relationship deterioration scores, independent and multiple regression analyses were performed for the presence or absence of difficulty implementing infection control measures, presence or absence of caregivers' mental health concerns, and the presence or absence of deterioration of one or more problematic behaviors. RESULTS: Overall, 84.1% of the children displayed difficulties implementing infection prevention measures. No relationship was observed between difficulty with infection prevention measures and deterioration in their relationships with parents and friends when schools were closed. After school reopened, however, deterioration in parent‒child relationships correlated positively with difficulty in hand-washing, and deterioration of friendships correlated positively with the maintenance of social distancing and difficulty in hand-washing. Deterioration of friendships correlated negatively with difficulty in voluntarily complying with stay-at-home requests. CONCLUSION: Difficulty in implementing infection prevention measures was related to deterioration in social relationships with parents and friends of children with neurodevelopmental disorders during the school reopening period, following COVID-19 school closure in Japan. Under a condition requiring heightened infection control, close monitoring may be necessary for the social relationships in children with neurodevelopmental disorders.

Alterations in brain networks in children with sub-threshold autism spectrum disorder: A magnetoencephalography study.

Individuals with sub-threshold autism spectrum disorder (ASD) are those who have social communication difficulties but do not meet the full ASD diagnostic criteria. ASD is associated with an atypical brain network; however, no studies have focused on sub-threshold ASD. Here, we used the graph approach to investigate alterations in the brain networks of children with sub-threshold ASD, independent of a clinical diagnosis. Graph theory is an effective approach for characterizing the properties of complex networks on a large scale. Forty-six children with ASD and 31 typically developing children were divided into three groups (i.e., ASD-Unlikely, ASD-Possible, and ASD-Probable groups) according to their Social Responsiveness Scale scores. We quantified magnetoencephalographic signals using a graph-theoretic index, the phase lag index, for every frequency band. Resultantly, the ASD-Probable group had significantly lower small-worldness (SW) in the delta, theta, and beta bands than the ASD-Unlikely group. Notably, the ASD-Possible group exhibited significantly higher SW than the ASD-Probable group and significantly lower SW than the ASD-Unlikely group in the delta band only. To our knowledge, this was the first report of the atypical brain network associated with sub-threshold ASD. Our findings indicate that magnetoencephalographic signals using graph theory may be useful in detecting sub-threshold ASD.

Effect of CNTNAP2 polymorphism on receptive language in children with autism spectrum disorder without language developmental delay.

AIM: The receptive language ability of individuals with autism spectrum disorder (ASD) seems to lag behind expressive language ability. Several autism-related genes may influence this developmental delay. Polymorphism of one such gene, namely, the contactin-associated protein-like 2 gene (CNTNAP2), affects receptive language in individuals with language delay. However, the association between CNTNAP2 polymorphism and receptive language in individuals with no language delay remains unclear. METHODS: We included 59 children with ASD and 57 children with typical development in this study and investigated this association using coarse-grained exact matching. RESULTS: We present the first evidence of an association between CNTNAP2 rs2710102 (A-allele carrier) and reduced receptive language ability in children with ASD whose language development was not delayed. Similarly, among children with typical development, A-allele carriers had lower receptive language ability, but the difference was non-significant. CONCLUSIONS: It is possible that the effect of rs2710102 on receptive language ability is larger in the presence of autism-related genes. Consequently, we speculate that the effect of rs2710102 on receptive language ability would be exerted in combination with other genes. These findings provide new insights into the genetic interactions between mutations associated with common language disorders and ASD and identify molecular mechanisms and risk alleles that contribute to receptive vocabulary. These findings also provide practical guidance in terms of providing candidate genetic markers that may provide opportunities for targeted early intervention to stratify risk and improve prognosis for poor receptive language development in children with ASD.

Relation between acquisition of lexical concept and joint attention in children with autism spectrum disorder without severe intellectual disability.

In children with autism spectrum disorder (ASD), impairment of joint attention and language function are observed frequently from early childhood. Earlier reports have described these two phenomena as mutually related. For this study, developing past research, the relation between joint attention and the ability of conceptual inference is examined in 113 Japanese children (67.9 months mean age, 75% male) with ASD. We calculated Pearson's correlation coefficients between their Joint attention abnormality evaluated by ADOS-2 and "Riddle" subscale in K-ABC, then they are negatively correlated: r (104) = -.285. A larger abnormality of joint attention is associated with a lower ability of conceptual inference. New findings were obtained indicating that, in children of this age group with ASD, the degree of joint attention impairment is correlated negatively with conceptual inference ability, but not with expressive and receptive language abilities. Consideration of the mechanism of this relation is presented in this report.

Altered sensory integration from body and language development in children with autism spectrum disorder.

Aim: Although atypical sensory motor processing has been investigated in children with autism spectrum disorder (ASD), whether or not atypical sensory motor processing is related to altered language function in children with ASD remains unclear. Methods: This study examined the relationship between sensory motor processing and language conceptual inference ability in 3-10-year-old children with (n = 61) and without (n = 114) ASD. Language performance was assessed using the language conceptual inference task of the Kaufman Assessment Battery for Children (K-ABC). Sensory processing was assessed using the Caregiver Sensory Profile. Results: In children with ASD, altered processing of the fine motor/perceptual factor scored by sensory profile was found to be significantly related to language conceptual inference ability in the K-ABC, representing the integrated abilities of language comprehension and language expression, which reflect language semantic concept formation. Conclusions: For children with ASD, the results suggest a relationship between difficulties of integrating sensory information perceived from the body adjusting fine movement and deficiencies of language semantic conceptual formation.

A common variant of CNTNAP2 is associated with sub-threshold autistic traits and intellectual disability.

Sub-threshold autistic traits are common in the general population. Children with sub-threshold autistic traits have difficulties with social adaptation. Contactin-associated protein-like 2 (CNTNAP2) is associated with the development of Autism spectrum disorder (ASD) and the single-nucleotide polymorphism rs2710102 (G/A) of CNTNAP2 is suggested to contribute to sub-threshold social impairments and intellectual disabilities. We recruited 67 children with Autistic disorder (AD) (49 boys, 18 girls, aged 38-98 months) and 57 typically developing (TD) children (34 boys, 23 girls, aged 53-90 months). We assessed the participants' intelligence and social reciprocity using the Kaufman Assessment Battery for Children (K-ABC) and the Social Responsiveness Scale (SRS), respectively. Genomic DNA was extracted from the buccal mucosa and genotyped for rs2710102. A chi-square test revealed a significant association between genotype and group [χ2(2) = 6.56, p = 0.038]. When a co-dominant model was assumed, the results from linear regression models demonstrated that TD children with A-carriers (AA + AG) presented higher SRS T-scores [t(55) = 2.11, p = 0.039] and lower simultaneous processing scale scores of K-ABC [t(55) = -2.19, p = 0.032] than those with GG homozygotes. These associations were not significant in children with ASD. TD children with the rs2710102 A-allele may have more sub-threshold autistic traits than those with GG homozygotes, reflected in higher SRS scores and lower simultaneous processing scale scores. These results support the use of genetic evidence to detect sub-threshold autistic traits.

Atypical Resting State Functional Neural Network in Children With Autism Spectrum Disorder: Graph Theory Approach.

Measuring whole brain networks is a promising approach to extract features of autism spectrum disorder (ASD), a brain disorder of widespread regions. Objectives of this study were to evaluate properties of resting-state functional brain networks in children with and without ASD and to evaluate their relation with social impairment severity. Magnetoencephalographic (MEG) data were recorded for 21 children with ASD (7 girls, 60-89 months old) and for 25 typically developing (TD) control children (10 girls, 60-91 months old) in a resting state while gazing at a fixation cross. After signal sources were localized onto the Desikan-Killiany brain atlas, statistical relations between localized activities were found and evaluated in terms of the phase lag index. After brain networks were constructed and after matching with intelligence using a coarsened exact matching algorithm, ASD and TD graph theoretical measures were compared. We measured autism symptoms severity using the Social Responsiveness Scale and investigated its relation with altered small-worldness using linear regression models. Children with ASD were found to have significantly lower small-worldness in the beta band (p = 0.007) than TD children had. Lower small-worldness in the beta band of children with ASD was associated with higher Social Responsiveness Scale total t-scores (p = 0.047). Significant relations were also inferred for the Social Awareness (p = 0.008) and Social Cognition (p = 0.015) sub-scales. Results obtained using graph theory demonstrate a difference between children with and without ASD in MEG-derived resting-state functional brain networks, and the relation of that difference with social impairment. Combining graph theory and MEG might be a promising approach to establish a biological marker for ASD.

Parenting Stress and Social Style in Mothers and Fathers of Children with Autism Spectrum Disorder: A Cross-Cultural Investigation in Italy and Japan.

Parents of children with autism spectrum disorder (ASD) face unique challenges, which may affect parenting functioning. However, little is known about gender and cultural variations in parenting stress and styles in these families. The aims of this study were to investigate: (1a) the differences in parenting stress and (1b) social style between Italian and Japanese mothers and fathers of children with ASD; (2) the predictive role of culture, sociodemographic, and child's characteristics on parenting stress; (3) the predictors of the social parenting style, including parenting stress dimensions. The study involved 92 Italians and 89 Japanese parents of school-age children (5-12 years) with ASD who completed the Parenting Stress Index and the Parenting Style Questionnaire. Results revealed that Japanese parents showed higher parenting stress and less engagement in social style than Italians. Across cultures, mothers used more social style than fathers. Being Japanese and having a child with greater ASD severity predicted higher levels of parenting stress. We also found that country, parent's gender, and stress related to the dysfunctional interaction were significant predictors of parenting social style. Our findings highlight the importance of a cross-cultural approach to better understand the experiences and needs of mothers and fathers of children with ASD.

Epileptiform discharges relate to altered functional brain networks in autism spectrum disorders.

Many individuals with autism spectrum disorders have comorbid epilepsy. Even in the absence of observable seizures, interictal epileptiform discharges are common in individuals with autism spectrum disorders. However, how these interictal epileptiform discharges are related to autistic symptomatology remains unclear. This study used magnetoencephalography to investigate the relation between interictal epileptiform discharges and altered functional brain networks in children with autism spectrum disorders. Instead of particularly addressing individual brain regions, we specifically examine network properties. For this case-control study, we analysed 70 children with autism spectrum disorders (52 boys, 18 girls, 38-92 months old) and 19 typically developing children (16 boys, 3 girls, 48-88 months old). After assessing the participants' social reciprocity using the Social Responsiveness Scale, we constructed graphs of functional brain networks from frequency band separated task-free magnetoencephalography recordings. Nodes corresponded to Desikan-Killiany atlas-based 68 brain regions. Edges corresponded to phase lag index values between pairs of brain regions. To elucidate the effects of the existence of interictal epileptiform discharges on graph metrics, we matched each of three pairs from three groups (typically developing children, children with autism spectrum disorders who had interictal epileptiform discharges and those who did not) in terms of age and sex. We used a coarsened exact matching algorithm and applied adjusted regression analysis. We also investigated the relation between social reciprocity and the graph metric. Results show that, in children with autism spectrum disorders, the average clustering coefficient in the theta band was significantly higher in children who had interictal epileptiform discharges. Moreover, children with autism spectrum disorders who had no interictal epileptiform discharges had a significantly lower average clustering coefficient in the theta band than typically developing children had. However, the difference between typically developing children and children with autism spectrum disorder who had interictal epileptiform discharges was not significant. Furthermore, the higher average clustering coefficient in the theta band corresponded to severe autistic symptoms in children with autism spectrum disorder who had interictal epileptiform discharges. However, the association was not significant in children with autism spectrum disorders who had no interictal epileptiform discharge. In conclusion, results demonstrate that alteration of functional brain networks in children with autism spectrum disorders depends on the existence of interictal epileptiform discharges. Interictal epileptiform discharges might 'normalize' the deviation of altered brain networks in autism spectrum disorders, increasing the clustering coefficient. However, when the effect exceeds tolerance, it actually exacerbates autistic symptoms.

Joint attention and intelligence in children with autism spectrum disorder without severe intellectual disability.

In children with autism spectrum disorder (ASD), joint attention is regarded as a predictor of language function, social skills, communication, adaptive function, and intelligence. However, existing information about the association between joint attention and intelligence is limited. Most such studies have examined children with low intelligence. For this study, we investigated whether joint attention is related to intelligence in young children with autism spectrum disorder (ASD) without severe intellectual disability. We analyzed 113 children with ASD aged 40-98 months. Their Kaufman Assessment Battery (K-ABC) Mental Processing Index (MPI) scores are 60 and more (mean 93.4). We evaluated their intelligence using K-ABC and evaluated their joint attention using ADOS-2. After we performed simple regression analyses using K-ABC MPI and its nine subscales as dependent variables, using joint attention as the independent variable, we identified joint attention as a positive predictor of the MPI and its two subscales. From this result, we conclude that joint attention is related to intelligence in young children with ASD without severe intellectual disability. This result suggests a beneficial effect of early intervention targeting joint attention for children with ASD. LAY SUMMARY: Joint attention is the ability to coordinate visual attention with another person and then shift one's gaze toward an object or event. Impairment of joint attention is regarded as an early marker of autism spectrum disorder (ASD). This study revealed impairment of joint attention as associated with lower intelligence in ASD children. These results are expected to constitute a rationale for future studies, particularly addressing beneficial effects of early intervention targeting joint attention for children with ASD.

Decreased grey matter volumes in unaffected mothers of individuals with autism spectrum disorder reflect the broader autism endophenotype.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an early onset and a strong genetic origin. Unaffected relatives may present similar but subthreshold characteristics of ASD. This broader autism phenotype is especially prevalent in the parents of individuals with ASD, suggesting that it has heritable factors. Although previous studies have demonstrated brain morphometry differences in ASD, they are poorly understood in parents of individuals with ASD. Here, we estimated grey matter volume in 45 mothers of children with ASD (mASD) and 46 age-, sex-, and handedness-matched controls using whole-brain voxel-based morphometry analysis. The mASD group had smaller grey matter volume in the right middle temporal gyrus, temporoparietal junction, cerebellum, and parahippocampal gyrus compared with the control group. Furthermore, we analysed the correlations of these brain volumes with ASD behavioural characteristics using autism spectrum quotient (AQ) and systemizing quotient (SQ) scores, which measure general autistic traits and the drive to systemize. Smaller volumes in the middle temporal gyrus and temporoparietal junction correlated with higher SQ scores, and smaller volumes in the cerebellum and parahippocampal gyrus correlated with higher AQ scores. Our findings suggest that atypical grey matter volumes in mASD may represent one of the neurostructural endophenotypes of ASD.

Shorter P1m Response in Children with Autism Spectrum Disorder without Intellectual Disabilities.

(1) Background: Atypical auditory perception has been reported in individuals with autism spectrum disorder (ASD). Altered auditory evoked brain responses are also associated with childhood ASD. They are likely to be associated with atypical brain maturation. (2) Methods: This study examined children aged 5-8 years old: 29 with ASD but no intellectual disability and 46 age-matched typically developed (TD) control participants. Using magnetoencephalography (MEG) data obtained while participants listened passively to sinusoidal pure tones, bilateral auditory cortical response (P1m) was examined. (3) Results: Significantly shorter P1m latency in the left hemisphere was found for children with ASD without intellectual disabilities than for children with TD. Significant correlation between P1m latency and language conceptual ability was found in children with ASD, but not in children with TD. (4) Conclusions: These findings demonstrated atypical brain maturation in the auditory processing area in children with ASD without intellectual disability. Findings also suggest that ASD has a common neural basis for pure-tone sound processing and language development. Development of brain networks involved in language concepts in early childhood ASD might differ from that in children with TD.

Aberrant brain oscillatory coupling from the primary motor cortex in children with autism spectrum disorders.

Autism spectrum disorder (ASD) often involves dysfunction in general motor control and motor coordination, in addition to core symptoms. However, the neural mechanisms underlying motor dysfunction in ASD are poorly understood. To elucidate this issue, we focused on brain oscillations and their coupling in the primary motor cortex (M1). We recorded magnetoencephalography in 18 children with ASD, aged 5 to 7 years, and 19 age- and IQ-matched typically-developing children while they pressed a button during a video-game-like motor task. The motor-related gamma (70 to 90 Hz) and pre-movement beta oscillations (15 to 25 Hz) were analyzed in the primary motor cortex using an inverse method. To determine the coupling between beta and gamma oscillations, we applied phase-amplitude coupling to calculate the statistical dependence between the amplitude of fast oscillations and the phase of slow oscillations. We observed a motor-related gamma increase and a pre-movement beta decrease in both groups. The ASD group exhibited a reduced motor-related gamma increase and enhanced pre-movement beta decrease in the ipsilateral primary motor cortex. We found phase-amplitude coupling, in which high-gamma activity was modulated by the beta rhythm in the primary motor cortex. Phase-amplitude coupling in the ipsilateral primary motor cortex was reduced in the ASD group compared with the control group. Using oscillatory changes and their couplings, linear discriminant analysis classified the ASD and control groups with high accuracy (area under the receiver operating characteristic curve: 97.1%). The current findings revealed alterations in oscillations and oscillatory coupling, reflecting the dysregulation of motor gating mechanisms in ASD. These results may be helpful for elucidating the neural mechanisms underlying motor dysfunction in ASD, suggesting the possibility of developing a biomarker for ASD diagnosis.

Participatory Art Activities Increase Salivary Oxytocin Secretion of ASD Children.

Autism spectrum disorder (ASD) occurs in 1 in 160 children worldwide. Individuals with ASD tend to be unique in the way that they comprehend themselves and others, as well as in the way that they interact and socialize, which can lead to challenges with social adaptation. There is currently no medication to improve the social deficit of children with ASD, and consequently, behavioral and complementary/alternative intervention plays an important role. In the present pilot study, we focused on the neuroendocrinological response to participatory art activities, which are known to have a positive effect on emotion, self-expression, sociability, and physical wellbeing. We collected saliva from 12 children with ASD and eight typically developed (TD) children before and after a visual art-based participatory art workshop to measure the levels of oxytocin, a neuropeptide involved in a wide range of social behaviors. We demonstrated that the rate of increase in salivary oxytocin following art activities in ASD children was significantly higher than that in TD children. In contrast, the change rate of salivary cortisol after participatory art activities was similar between the two groups. These results suggest that the beneficial effects of participatory art activities may be partially mediated by oxytocin release, and may have therapeutic potential for disorders involving social dysfunction.

Brain responses to human-voice processing predict child development and intelligence.

Children make rapid transitions in their neural and intellectual development. Compared to other brain regions, the auditory cortex slowly matures, and children show immature auditory brain activity. This auditory neural plasticity largely occurs as a response to human-voice stimuli, which are presented more often than other stimuli, and can even be observed in the brainstem. Early psychologists have proposed that sensory processing and intelligence are closely related to each other. In the present study, we identified brain activity related to human-voice processing and investigated a crucial neural correlate of child development and intelligence. We also examined the neurophysiological activity patterns during human-voice processing in young children aged 3 to 8 years. We investigated auditory evoked fields (AEFs) and oscillatory changes using child-customized magnetoencephalography within a short recording time (<6 min). We examined the P1m component of AEFs, which is a predominant component observed in young children. The amplitude of the left P1m was highly correlated with age, and the amplitude of the right P1m was highly correlated with the intelligence quotient. For auditory-related oscillatory changes, we found a positive correlation between the intelligence quotient and percent change of gamma increase relative to baseline in the right auditory cortex. We replicated the finding of age-related changes in auditory brain activity in young children, which is related to the slow maturation of the auditory cortex. In addition, these results suggest a close link between intelligence and auditory sensory processing, especially in the right hemisphere.

[Hematemesis due to rupture of splenic artery pseudoaneurysm in association with segmental arterial mediolysis:a case report].

A gastric ulcer was detected in a 54-year-old man who underwent upper gastrointestinal endoscopy for hematemesis. An abdominal contrasted computed tomography scan detected a splenic artery aneurysm adjacent to the gastric wall. Endoscopic hemostasis was thought to be risky owing to possible rupture of the aneurysm. Rupture of a splenic artery pseudoaneurysm due to segmental arterial mediolysis (SAM) was diagnosed by abdominal angiography, and subsequently transcatheter arterial embolization was performed. In cases of upper gastrointestinal hemorrhage, hemostasis is often performed during the emergency endoscopic examination. However, in cases of massive gastrointestinal bleeding, the possibility of a splenic artery aneurysm, in association with SAM, should be recognized. The risk of rupturing the aneurysm should be considered in selecting the most suitable treatment.

[Intraductal papillary neoplasm of bile duct developed in a patient with IgG4-related sclerosing cholangitis, autoimmune pancreatitis, and myasthenia gravis].

In the course of treatment for myasthenia gravis, enlargement of a cystic mass in the liver with peripheral bile duct dilation, diffuse pancreatic enlargement, and serum IgG4 level elevation was identified in a 65-year-old man. Following the diagnosis of autoimmune pancreatitis, a left hepatectomy was performed because of suspected malignancy of the cystic lesion. Analysis of the resected specimen revealed the cystic lesion to be a dilated bile duct. Intraductal papillary tumor comprising fibrovascular stalks covered by neoplastic epithelium was identified in the lesion. Infiltration of IgG4-positive plasma cells was discovered around the cystic lesion. Finally, a diagnosis of intraductal papillary neoplasm of bile duct with IgG4-related sclerosing cholangitis was made. Autoimmune diseases, including IgG4-related diseases, require careful observation because of their potential for malignancy.