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Chronic granulomatous disease (CGD) is an inborn error of immunity caused by inactivating genetic mutations in any one of the components of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Phagocytic cell reactive oxygen species generation is impaired in the absence of a functional NADPH oxidase complex. As a result, patients with CGD are at high risk of developing deep-seated infections with certain bacteria and fungi. Additionally, aberrant inflammation and granuloma formation may occur in multiple organs including the bowels, with inflammatory bowel disease seen as a common inflammatory complication of CGD. Traditionally, TNF-α inhibitors are considered effective biological therapies for moderate-to-severe inflammatory bowel disease. While limited case series and reports of patients with CGD have shown improvement in fistula healing with use of TNF-α inhibitors, several patients have developed severe, even fatal, infections with CGD-related pathogens while on TNF-inhibitor therapy. In this case report, we describe an adolescent male with X-linked CGD and steroid-refractory colitis with perirectal fistula and abscesses, who was initiated on treatment with infliximab, a TNF-α inhibitor. Following his first two infliximab doses, the patient developed a Candida glabrata lymphadenitis and associated ulcerating oropharyngeal lesions, requiring hospitalization and therapy with amphotericin B for resolution. We compare our patient's case to prior reports of infliximab use in CGD-related inflammatory bowel disease.

Objective: Cow's milk allergy (CMA) is a common allergic disease. Probiotics have been suggested as a treatment for CMA, with Lactobacillus rhamnosus GG (LGG) being one of the important predominant choices. Despite reports on this topic, the effectiveness of application in CMA remains to be firmly established. Methods: To assess the effects of LGG on CMA in children, the PubMed/Medline, Embase, Cochrane Library, and Web of Science databases were searched for studies on LGG in treatment of CMA, which were published in the English language. Results: Ten studies were finally included. Significantly higher tolerability rates favoring LGG over controls were observed [risk ratio (RR), 2.22; 95% confidence interval (CI), 1.86-2.66; I 2 = 0.00; moderate-quality evidence]. There were no significant differences in SCORAD values favoring LGG over the placebo (mean difference, 1.41; 95% CI, -4.99-7.82; p = 0.67; very low-quality evidence), and LGG may have improved fecal occult blood (risk ratio, 0.36; 95% CI, 0.14-0.92; p = 0.03; low-quality evidence). Conclusion: We found that LGG may have moderate-quality evidence to promote oral tolerance in children with CMA and may facilitate recovery from intestinal symptoms. However, this finding must be treated with caution, and more gpowerful RCTs are needed to evaluate the most effective dose and treatment time for children with CMA. Registration number: CRD42021237221.

Background: Mitochondrial dynamics, including mitochondrial fission and fusion, transport and distribution, biogenesis and degradation, are critical to neuronal function. The dynamin-1 like (DNM1L) gene encodes dynamin-related protein 1 (DRP1/DLP1), which is an evolutionarily conserved member of the dynamin family and is responsible for mitochondrial division. DNM1L variants can lead to mitochondrial fission dysfunction and neurological disorders. Methods: We report a case of DNM1L-related mitochondrial disease admitted to Tianjin Children's Hospital. We searched for similar reported cases in the PubMed database using the terms "DNM1L" and "mitochondrial," reviewed recent literature to summarize the clinical and genetic characteristics, and analyzed genotype-phenotype correlations. Results: The patient presented with psychomotor retardation, motor disturbance (muscle weakness with paroxysmal hypermyotonia), and a de novo variant (c.116G>A, g.22229G>A, p.S39N) in the GTPase domain of DNM1L (reference sequence NM_012062), which has not previously been reported in the literature. This case was combined with an additional 35 cases identified in 20 relevant references in order to analyze a total of 36 patients. The male-to-female ratio was 1:1.06, and the median age of onset was 6 months (range, neonatal period to 9 years). The cardinal symptoms included psychomotor retardation in 77.8% (28/36), limb paralysis in 66.7% (18/27), dystonia in 82.8% (24/29), and epilepsy in 59.4% (19/32). The clinical manifestations of variants in the GTPase domain of DRP1 were milder than those identified in the middle domain. Conclusion: This case report describes a new variant of the DNM1L gene, and summarizes previously reported cases. Furthermore, the clinical phenotype and the genotype of DNM1L gene-associated mitochondrial disease was analyzed to improve the understanding of this disease.

Duplications of chromosome 8p lead to rare genetic conditions characterized by variable phenotypes. 8p21 and 8p23 duplications were associated with mental retardation but only 8p23 duplication was associated with heart defects. 8p22→ p21.3 duplications were associated with an autism spectrum disorder in several cases. We present a rare case with a de novo duplication of the entire 8p21.3→ p23.3 region, documented by karyotype, FISH, and array CGH, with t(4;8)(q35;p21.3) translocation in a 7 years-old girl. She was referred for genetic counseling at the age of 20 months due to mild dysmorphic facial features, psychomotor retardation, and a noncyanotic heart defect. Another examination carried out at the age of 5 years, enabled the diagnosis of autism spectrum disorder and attention deficit hyperactivity disorder. Upon re-examination after two years she was diagnosed with autism spectrum disorder, attention deficit hyperactivity disorder, liminal intellect with cognitive disharmony, delay in psychomotor acquisitions, developmental language delay, an instrumental disorder, and motor coordination disorder. Cytogenetic analysis using GTG technique revealed the following karyotype: 46,XX,der(4),t(4;8)(q35;p21.3). The translocation of the duplicated 8pter region to the telomeric region 4q was confirmed by FISH analysis (DJ580L5 probe). Array CGH showed: arr[GRCh37]8p23.3p21.3(125733_22400607) × 3. It identified a terminal duplication, a 22.3 Mb copy number gain of chromosome 8p23.3-p21.3, between 125,733 and 22,400,607. In this case, there is a de novo duplication of a large chromosomal segment, which was translocated to chromosome 4q. Our report provides additional data regarding neuropsychiatric features in chromosome 8p duplication. The phenotypic consequences in our patient allow clinical-cytogenetic correlations and may also reveal candidate genes for the phenotypic features.

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS, OMIM#603736) and genitopatellar syndrome (GTPTS, OMIM#606170), characterized by global developmental delay/intellectual disability and special clinical manifestations, are two distinct clinically overlapping syndromes caused by truncating sequence variants in the KAT6B (10q22.2) gene. We detected a de novo heterozygous variant within exon 16 of KAT6B (Chr10p: 76781966-76781967) in a 7-months-old female infant who showed symptoms of short stature, global developmental delay, blepharophimosis, and lacrimal duct anomalies highly consistent with SBBYSS. Following the clinical features, we analyzed the KAT6B gene using Next Generation Sequencing (NGS) techniques. Her parents didn't present the same genetic variant. The patient we reported here is mainly characterized by syndromic forms of short stature and developmental delay, which may contribute to the understanding of clinical genetics for KAT6B-associated disorders.

Infection with varicella zoster virus (VZV) is usually a benign and self-limiting disease. Serious complications by bacterial pathogens do occur, such as necrotising fasciitis (NF). One of the most important is Streptococcus pyogenes (or Group A Streptococcus, GAS), which colonizes epithelial surfaces, primarily of the throat and skin. In rare instances, varicella may also be associated with S. pyogenes endocarditis. Review of the literature reveals only 18 children with infective endocarditis (IE) caused by GAS since 1942. VZV as antecedent illness was found in five (28%). Fourteen (78%) had no pre-existing cardiac abnormalities. Death occurred in three (17%) children. Infective endocarditis with acute deterioration secondary to rupture of mitral valve chordae tendineae necessitating cardiac surgery has not been reported in the literature yet. We present this rare and instructive pediatric case and the results of a literature search on S. pyogenes endocarditis in children.

Background: Congenital diaphragmatic hernia (CDH) is a rare defect of the diaphragm commonly associated with high morbidity and mortality due to lung hypoplasia and pulmonary hypertension. Although in 70% of patients the etiology of a CDH remains unknown, a multitude of causative chromosomal aberrations has been identified. Case presentation: We describe the first case of isolated 11p15 duplication with CDH. The 18.6 Mb large duplication affected 285 RefSeq genes and included the Beckwith-Wiedemann (BWS)-associated imprinting control region 2 (ICR2, KCNQ1OT1 TSS DMR), whereas the ICR1 (H19 TSS DMR) was not affected. We were able to demonstrate de novo occurrence of the duplication. The paternal origin of the chromosomal material was detected by methylation testing the ICR2. Corresponding to other patients with duplications of the paternal ICR2 copy, a BWS phenotype is not present. Conclusions: The patient presented here together with the review of four other cases from the literature indicate an association between duplications of the chromosomal region 11p15 and developmental defects of the diaphragm. Thus, we suggest duplications of 11p15 as a rare cause of CDH. This association may or may not appear in the context of BWS depending on the extent of the duplication and the imprinting status. Hence, a genetic workup should be performed in patients with CDH, particularly when other abnormalities are noted.

Pontocerebellar hypoplasia (PCH) type 2 is a very rare autosomal recessive neurodegenerative disorder with prenatal onset that disrupts brain development. We present three patients (two siblings and one unrelated child) with PCH 2 linked to the most common mutation c.919G > T (p.Ala307Ser) in TSEN54 gene. The disease started soon after birth with feeding difficulties, extrapyramidal symptoms, psychomotor retardation, progressive microcephaly. Two of the patients were diagnosed with dyskinetic cerebral palsy (CP) at first. Despite the neurodegenerative character of PCH 2, the absence of regression and even some developmental progress in few patients, might erroneously lead to the incorrect diagnosis of dyskinetic CP. Megacisterna magna on brain ultrasound makes the diagnosis of PCH 2 highly probable and should prompt further imaging with MRI. MRI findings of PCH are pivotal for the diagnosis. Genetic testing for the most common mutation in TSEN54 gene should also be performed. Correct diagnosis of PCH 2 is essential not only for the prognosis of the patient, but also for prenatal diagnosis in future pregnancies. Knowledge of the clinical picture of PCH 2 will lead to correct and timely diagnosis. Advanced neuroimaging procedures and molecular genetic techniques provide valuable tools for prompt diagnosis of rare, but clinically important, neurogenetic imitators of CP.

Immunosuppressive therapy is a known risk factor for opportunistic infections. We report the first case of severe Pneumocystis jirovecii infection requiring intensive care in a pediatric patient with inflammatory bowel disease (IBD). The literature was reviewed and there were 92 reported cases of Pneumocystis pneumonia (PCP) in patients with IBD. Most sources were case reports and there was likely reporting bias toward patients receiving immunomodulators, anti-tumor necrosis factor (anti-TNF) therapy, and those who died. Overall, 56% of patients were males and 58% had Crohn's disease. The median age was 45 years (interquartile range 30-68, range 8-78) and 86% of patients were lymphopenic. The case-fatality rate was 23%. Corticosteroids were used as IBD treatment in 88% of patients who subsequently developed PCP, 42% received thiopurines, 44% used anti-TNF therapy, and 15% received either cyclosporine or tacrolimus. Rates of mono, dual, triple, and quadruple immunosuppression therapy were 35, 35, 29, and 2%, respectively. This report highlights the importance of considering PCP in immunosuppressed lymphopenic pediatric IBD patients who present with unusual symptoms. Moreover, it should give gastroenterologists the impetus to limit immunosuppressive therapy to its minimal effective dose and consider options such as exclusive enteral nutrition wherever possible. Although there is no place for global PCP prophylaxis in IBD given the low incidence, in an era when there is increasing use of biologic agents with combination immunosuppressive therapy, the risk-benefit profile of PCP chemoprophylaxis should be revisited in selected cohorts such as patients on triple immunosuppression with corticosteroids, thiopurines, and a biological agent or calcineurin inhibitor, especially in lymphopenic individuals.