IL-6-specific autoantibodies among APECED and thymoma patients

Peer reviewe

Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines

Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A–producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis

Adult Height in Patients with Advanced CKD Requiring Renal Replacement Therapy during Childhood.

BACKGROUND AND OBJECTIVES: Growth and final height are of major concern in children with ESRD. This study sought to describe the distribution of adult height of patients who started renal replacement therapy (RRT) during childhood and to identify determinants of final height in a large cohort of RRT children. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 1612 patients from 20 European countries who started RRT before 19 years of age and reached final height between 1990 and 2011 were included. Linear regression analyses were performed to calculate adjusted mean final height SD score (SDS) and to investigate its potential determinants. RESULTS: The median final height SDS was -1.65 (median of 168 cm in boys and 155 cm in girls). Fifty-five percent of patients attained an adult height within the normal range. Adjusted for age at start of RRT and primary renal diseases, final height increased significantly over time from -2.06 SDS in children who reached adulthood in 1990-1995 to -1.33 SDS among those reaching adulthood in 2006-2011. Older age at start of RRT, more recent period of start of RRT, cumulative percentage time on a functioning graft, and greater height SDS at initiation of RRT were independently associated with a higher final height SDS. Patients with congenital anomalies of the kidney and urinary tract and metabolic disorders had a lower final height than those with other primary renal diseases. CONCLUSIONS: Although final height remains suboptimal in children with ESRD, it has consistently improved over time

AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies

APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.Peer reviewe

Psychosocial impact of structured transfer of adolescents with kidney transplants to adult services

Background: Pediatric kidney transplantation entails a well-timed transition from pediatric to adult medical care. We aimed to construct a structured transition protocol and evaluate its impact on transfer-related psychosocial problems in Slovenian patients with kidney transplants. Methods: Individual transition-related perceptions of our patients and their parents were first assessed, and the gathered information was used to establish a country-specific transition protocol. Eleven kidney transplant patients qualified for actual transfer and were considered for further analysis. Comprehension and attitude towards transfer, coping strategies, personality resilience, behavioral, and emotional problems were assessed using questionnaires and established psychological tools before and after the completed transfer. The results were compared and analyzed. Results: Ten of the eleven eligible patients were transferred to adult services between April 2020 and January 2021. The median age at enrollment was 19.7 years (range: 18.2–22.8 years). The most frequent concerns regarding upcoming health care were worse accessibility (50%), less supportive and less committed healthcare providers (40%), and deterioration of medical condition (10.0%). After the completed protocol-guided transfer, the patients declared to have no further concerns or worries. Before transfer, 28.9% of the patients\u27 responses rated the amount and relevance of received information and counseling as “Adequate” or “Very adequate,” whereas, after the transfer, the proportion of positive responses increased to 48.9%. Anxiety and withdrawn depressive symptoms were the predominant emotional problems before transfer. Their prevalence decreased after the completed transfer. Conclusions: Our results suggest that transfer-related anxieties and concerns can be significantly reduced by applying a structured transition protocol in transplant patients

Unraveling the etiology of pediatric vertigo and dizziness

Background and Objectives: Numerous authors have reported that the commonest type of vertigo in children is migraine-associated vertigo (vestibular migraine and benign paroxysmal vertigo of childhood—BPV). We aimed to provide the possible etiological background of vertigo and dizziness in Slovenian children. Materials and Methods: A retrospective case series of pediatric vertigo and dizziness children referred to the tertiary pediatric otorhinolaryngology center from 2015 to 2020. Children received a complete audiological and vestibular workup and were referred to pediatric specialists depending on the clinical presentation. Results: Of 257 children (42% male, 58% female) aged 1–17 years (M = 10.9, SD = 4.3 years) in 19.1% vertigo and dizziness were classified as central, in 12.4% as a peripheral vestibular, in 10.9% as a hemodynamic, in 5.8% as a psychological and none as visual by pediatric neurologists, otorhinolaryngologists, cardiologists, psychologists or ophthalmologists, respectively. 40.8% (20) children with central vertigo had BPV (7.8% of all children) and 8.2% (4) migrainous vertigo. In 43.6% (112 children), the etiology remained unclassified. Conclusions: After a thorough multidisciplinary workup, the etiology of vertigo and dizziness was unraveled in the majority of children referred to our tertiary otorhinolaryngology center. The most common cause was centralhowever, in a considerable number, the etiology remained unclassified. The latter could be attributed to the self-limiting nature of vertigo spells. Hence, a child presenting with dizziness and vertigo requires a multidisciplinary approach, in which referral to a neurologist is, in most cases, essential

The importance of early genetic diagnostics of hearing loss in children

Hearing loss is one of the most common sensory deficits. It carries severe medical and social consequences, and therefore, universal newborn hearing screening was introduced at the beginning of this century. Affected patients can have hearing loss as a solitary deficit (non-syndromic hearing loss) or have other organs affected as well (syndromic hearing loss). In around 60% of cases, congenital hearing loss has a genetic etiology, where disease-causing variants can change any component of the hearing pathway. Genetic testing is usually performed by sequencing. Sanger sequencing enables analysis of the limited number of genes strictly preselected according to the clinical presentation and the prevalence among the hearing loss patients. In contrast, next-generation sequencing allows broad analysis of the numerous genes related to hearing loss, exome, or the whole genome. Identification of the genetic etiology is possible, and it makes the foundation for the genetic counselling in the family. Furthermore, it enables the identification of the comorbidities that may need a referral for specialty care, allows early treatment, helps with identification of candidates for cochlear implant, appropriate aversive/protective management, and is the foundation for the development of novel therapeutic options

Novel GRHL2 gene variant associated with hearing loss

In contrast to the recessive form, hearing loss inherited in a dominant manner is more often post-lingual and typically results in a progressive sensorineural hearing loss with variable severity and late onset. Variants in the GRHL2 gene are an extremely rare cause of dominantly inherited hearing loss. Genetic testing is a crucial part of the identification of the etiology of hearing loss in individual patients, especially when performed with next-generation sequencing, enabling simultaneous analysis of numerous genes, including those rarely associated with hearing loss. We aimed to evaluate the genetic etiology of hearing loss in a family with moderate late-onset hearing loss using next-generation sequencing and to conduct a review of reported variants in the GRHL2 gene. We identified a novel disease-causing variant in the GRHL2 gene (NM_024915: c.1510C>Tp.Arg504Ter) in both affected members of the family. They both presented with moderate late-onset hearing loss with no additional clinical characteristics. Reviewing known GRHL2 variants associated with hearing loss, we can conclude that they are more likely to be truncating variants, while the associated onset of hearing loss is variable