NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency.

PURPOSE: Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system. METHODS: Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system. RESULTS: Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell-intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia. CONCLUSION: In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.

Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients.

PURPOSE: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. METHODS: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. RESULTS: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the ß-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: ß-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH). CONCLUSION: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

CAIPIRINHA-accelerated T1w 3D-FLASH for small-bowel MR imaging in pediatric patients with Crohn's disease: assessment of image quality and diagnostic performance.

BACKGROUND: The "Controlled Aliasing In Parallel Imaging Results In Higher Acceleration" (CAPIRINHA) technique greatly accelerates T1w 3D fast low angle shot (FLASH) scans while maintaining high image quality. We studied image quality and conspicuity of inflammatory lesions on CAIPIRINHA-accelerated imaging for pediatric small-bowel magnetic resonance imaging (MRI). METHODS: Forty-four consecutive patients (mean 14±3 years, 18 girls) underwent small-bowel MRI (MR enterography, MRE) at 1.5 T including diffusion-weighted imaging (DWI), contrast-enhanced CAIPIRINHA 3D-FLASH and standard 2D-FLASH imaging. Crohn's disease (CD) was confirmed in 26 patients, 18 patients served as control. Independent blinded readings were performed for grading of image quality and conspicuity of CD lesions on CAIPIRINHA FLASH and standard FLASH images in comparison to a reference standard comprising imaging and endoscopic data. RESULTS: CAIPIRINHA FLASH yielded significantly higher image quality with good inter-observer agreement (κ=0.68) and showed better visual delineation in 40% of the assessed bowel lesions, as compared to standard FLASH. There was full agreement for identification of CD patients between CAIPIRINHA and standard FLASH. CAIPIRINHA FLASH detected two small-bowel lesions that were not seen on standard FLASH. DWI revealed additional inflammatory lesions inconspicuous on contrast-enhanced imaging. MRE showed an overall diagnostic accuracy of 93%. CONCLUSION: We present first evidence that CAIPIRINHA greatly accelerates T1w imaging in paediatric MRE without trade-off in image quality or lesion conspicuity and is thus preferable to standard FLASH imaging.

Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts.

BACKGROUND: Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency and in about 50% the etiology remains unknown. Recently biallelic mutations in NBAS were identified as a new molecular cause of ALF with onset in infancy, leading to recurrent acute liver failure (RALF). METHODS: The phenotype and medical history of 14 individuals with NBAS deficiency was studied in detail and functional studies were performed on patients' fibroblasts. RESULTS: The phenotypic spectrum of NBAS deficiency ranges from isolated RALF to a multisystemic disease with short stature, skeletal dysplasia, immunological abnormalities, optic atrophy, and normal motor and cognitive development resembling SOPH syndrome. Liver crises are triggered by febrile infections; they become less frequent with age but are not restricted to childhood. Complete recovery is typical, but ALF crises can be fatal. Antipyretic therapy and induction of anabolism including glucose and parenteral lipids effectively ameliorates the course of liver crises. Patients' fibroblasts showed an increased sensitivity to high temperature at protein and functional level and a disturbed tethering of vesicles, pointing at a defect of intracellular transport between the endoplasmic reticulum and Golgi. CONCLUSIONS: Mutations in NBAS cause a complex disease with a wide clinical spectrum ranging from isolated RALF to a multisystemic phenotype. Thermal susceptibility of the syntaxin 18 complex is the basis of fever dependency of ALF episodes. NBAS deficiency is the first disease related to a primary defect of retrograde transport. Identification of NBAS deficiency allows optimized therapy of liver crises and even prevention of further episodes.

Peroral Endoscopic Myotomy for the Treatment of Achalasia in a 10-Year-Old Male Patient.

Peroral endoscopic myotomy (POEM) is a new endoscopic treatment for achalasia with very good short-term results in adults. Data about POEM in pediatric patients are missing. We present the case of a 10-year-old male patient with type I (classic) achalasia, successfully treated with POEM. The procedure was accomplished in a similar fashion to the technique used in adults. Short-term results were fine, with a complete control of dysphagia and absence of reflux. We suggest that POEM is a suitable option in pediatric patients-similar to adults-but long-term results must be awaited.

Small-bowel MRI in children and young adults with Crohn disease: retrospective head-to-head comparison of contrast-enhanced and diffusion-weighted MRI.

BACKGROUND: Small-bowel MRI based on contrast-enhanced T1-weighted sequences has been challenged by diffusion-weighted imaging (DWI) for detection of inflammatory bowel lesions and complications in patients with Crohn disease. OBJECTIVE: To evaluate free-breathing DWI, as compared to contrast-enhanced MRI, in children, adolescents and young adults with Crohn disease. MATERIALS AND METHODS: This retrospective study included 33 children and young adults with Crohn disease ages 17 ± 3 years (mean ± standard deviation) and 27 matched controls who underwent small-bowel MRI with contrast-enhanced T1-weighted sequences and DWI at 1.5 T. The detectability of Crohn manifestations was determined. Concurrent colonoscopy as reference was available in two-thirds of the children with Crohn disease. RESULTS: DWI and contrast-enhanced MRI correctly identified 32 and 31 patients, respectively. All 22 small-bowel lesions and all Crohn complications were detected. False-positive findings (two on DWI, one on contrast-enhanced MRI), compared to colonoscopy, were a result of large-bowel lumen collapse. Inflammatory wall thickening was comparable on DWI and contrast-enhanced MRI. DWI was superior to contrast-enhanced MRI for detection of lesions in 27% of the assessed bowel segments and equal to contrast-enhanced MRI in 71% of segments. CONCLUSION: DWI facilitates fast, accurate and comprehensive workup in Crohn disease without the need for intravenous administration of contrast medium. Contrast-enhanced MRI is superior in terms of spatial resolution and multiplanar acquisition.

Association of chronic non-bacterial osteomyelitis with Crohn's disease but not with CARD15 gene variants.

Chronic non-bacterial osteomyelitis (CNO) is an inflammatory, non-infectious disorder of the skeletal system with unknown etiology. Besides bone-inflammation, patients may present with inflammatory involvement of other tissues. Chronic recurrent multifocal osteomyelitis (CRMO) is the most severe form of CNO. We describe the occurrence of Crohn's disease (CD) in four patients, previously diagnosed with CRMO. Mutations in CARD15, encoding the NOD2 protein, have recently been found in patients with CD. Based on the occurence of CNO and CD in these four and several reported patients, we hypothesized that CD and CRMO might share a common autoinflammatory process. Thus, we searched for CD associated CARD15 gene variants R702W, G908R and 1007fs in 29 CNO patients, 4 of them additionally diagnosed with CD. In the latter one out of the four showed compound heterozygosity for the gene variants R702W and 1007fs. The allele frequency in the 25 patients diagnosed with CNO but not CD was not different from that already reported in healthy people (R702W 4.0%, G908R 2.0%, 1007fs 2.0%). The occurrence of non-bacterial bone inflammation and granulomatous intestinal inflammation seems to represent an extended phenotype of CD, which partly might be explained by potential disease causing mutations in CARD15. However, CNO without intestinal inflammation is not associated with common CARD15 gene variants. Therefore, other variants of genes coding for proteins involved in innate immunity and inflammation might predispose for the occurrence of CNO.

Chronic recurrent multifocal osteomyelitis: what is it and how should it be treated?

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is the most severe form of chronic nonbacterial osteomyelitis. In children and adolescents, chronic nonbacterial osteomyelitis predominantly affects the metaphyses of the long bones, but lesions can occur at any site in the skeleton. Other organs (the skin, eyes, gastrointestinal tract and lungs) can also be affected. Clinical diagnosis is often difficult because the symptoms and course of disease vary significantly. We present a 10-year-old girl diagnosed with CRMO involving several vertebrae, the femur and the metatarsus. INVESTIGATIONS: Physical examination, abdominal ultra sonography, conventional X-ray, MRI, technetium bone scan, esophagogastroduodenoscopy, colonoscopy, tests for HLA-B27 and thiopurine methyltransferase, polymerase chain reaction and thoracic vertebral bone biopsies. DIAGNOSIS: CRMO and Crohn's disease. MANAGEMENT: The patient's condition improved whilst being treated with NSAIDs for 3 months; however, the patient had an allergic skin reaction to this therapy. Treatment was switched to sulfasalazine, accompanied by 3 weeks of therapy using oral prednisone, but sulfasalazine was discontinued 2 months later because the patient exhibited a minor elevation in the levels of liver enzymes. The patient was free of musculoskeletal symptoms for 6 months, at which time she started to complain again about pain in her back and bowel. Multimodal therapy, consisting of mesasalazine, corticosteroids (budesonide) and azathioprine, induced clinical remission of Crohn's disease.