Anti-ZSCAN1 Autoantibodies Are a Feasible Diagnostic Marker for ROHHAD Syndrome Not Associated with a Tumor.
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SUBMITTER: Nakamura-Utsunomiya A
PROVIDER: S-EPMC10855538 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Anti-ZSCAN1 Autoantibodies Are a Feasible Diagnostic Marker for ROHHAD Syndrome Not Associated with a Tumor.
Nakamura-Utsunomiya Akari A Yamaguchi Kei K Goshima Naoki N
International journal of molecular sciences 20240201 3
Recent studies have reported the presence of autoantibodies against zinc finger and SCAN domain-containing protein 1 (ZSCAN1) in the sera of patients with rapid-onset obesity with hypoventilation, hypothalamic and autonomic dysregulation (ROHHAD) syndrome associated with neuroendocrine tumors, suggesting immunologic and paraneoplastic processes as the pathologic underpinnings. Moreover, several hypothalamic regions, including the subfornical organ (SFO), were reported to exhibit antibody reactiv ...[more]
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Project description:IntroductionThe diagnostic value of 7 tumor-associated autoantibodies (AABs) including p53, PGP9.5, SOX2, GAGE7, GBU4-5, MEGEA1, and CAGE for the detection of lung cancer has shown inconsistency in several studies. This study aimed to confirm the diagnostic value of 7AABs and to explore whether the diagnostic value would be improved by combining them with 7 traditional tumor-associated antigens (CEA, NSE, CA125, SCC, CA15-3, pro-GRP, and CYFRA21-1) in clinical settings.MethodsThe plasma levels of 7-AABs were detected by enzyme-linked immunosorbent assay (ELISA) in 533 lung cancer cases and 454 controls. The 7 tumor antigens (7-TAs) were measured by Electrochemiluminescence immunoassay with Cobas 6000 (Roche, Basel, Switzerland).ResultsThe positive rate of 7-AABs in the lung cancer group (64.00%) was significantly higher than that of healthy controls (47.90%). The 7-AABs panel was able to discriminate lung cancer from controls with a specificity of 51.50%. After combining the 7-AABs with 7-TAs, the sensitivity showed a significantly enhancement compared with 7AABs panel alone (92.09% vs 63.21%). In patients with resectable lung cancer, the combination of 7-AABs and 7-TAs improved the sensitivity from 63.52% to 97.42.DiscussionIn conclusion, our study found that the diagnostic value of 7-AABs was enhanced when combined with 7-TAs. This combined panel could be used as promising biomarker to detect resectable lung cancer in clinical settings.
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Project description:Mesothelioma is an aggressive tumor arising from the mesothelium, and is usually associated with previous exposure to asbestos. The incubation period of the tumor may be described as 30-40 years, and the prognosis is dismal. We previously discovered the Erc (Expressed in renal carcinoma) gene in the Eker rat model (Tsc2 gene mutant) and it was a homolog of the human mesothelin/MPF gene. We developed a novel ELISA system (N-ERC/mesothelin). Recently, we found that N-ERC/mesothelin was a potentially useful diagnostic marker for asbestos-related mesothelioma.
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Project description:ContextAnti-DFS70 antibodies are the most frequent antinuclear antibodies (ANA) found in healthy individuals. We assessed the clinical significance of the presence of anti-DFS70 antibodies.MethodsWe defined a group of patients (n = 421) with anti-DFS70 antibodies and a group of patients (n = 63) with a history of idiopathic arterial and/or venous thrombotic disease and/or obstetric complication (i.e. ≥ 3 miscarriages, fetal death or premature birth with eclampsia). Anti-DFS70 antibodies prevalence was also assessed in a cohort of 300 healthy blood donors.ResultsThe prevalence of thrombotic disease and/or obstetric complication in the 421 patients with anti-DFS70 antibodies was 13.1% (n = 55) and the prevalence of connective tissue disease was 19% (n = 80). Among the 63 patients with a history of thrombosis and/or obstetric complications, 7 (11.1%) had anti-DFS70 antibodies and among the latter, 5 had no common thrombophilic factor. In contrast, the prevalence of anti-DFS70 antibodies was of 3.0% (9 out of 300) in healthy donors. Finally, the Activated Partial Thromboplastin Time (aPTT) ratio of patients with a history of thrombosis and anti-DFS70 antibodies was lower than the aPTT ratio of other patients, suggesting that thrombotic patients with anti-DFS70 antibodies may have a hypercoagulable state.ConclusionWe described here for the first time an immune procoagulant state involving anti-DFS70 antibodies.
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Project description:Context: ROHHAD syndrome presents a significant resemblance to HIDEA syndrome. The latter is caused by biallelic loss-of-function variants in the P4HTM gene and encompasses hypotonia, intellectual disabilities, eye abnormalities, hypoventilation, and dysautonomia. We report the first patient identified with HIDEA syndrome from our ROHHAD cohort. Clinical case: Our patient was a 21-month-old girl who had a history of severe respiratory infections requiring intensive care, hypotonia, abnormal eye movements, and rapid weight gain. Polysomnography identified severe central hypoventilation. During her follow-up, a significant psychomotor delay and the absence of language were gradually observed. The prolactin levels were initially increased. Hypothermia was reported at 4 years. Exome sequencing identified a new homozygous truncating P4HTM variant. Discussion: Our patient met the diagnosis criteria for ROHHAD, which included rapid weight gain, central hypoventilation appearing after 1.5 years of age, hyperprolactinemia suggesting hypothalamic dysfunction, and autonomic dysfunction manifesting as strabismus and hypothermia. However, she also presented with severe neurodevelopmental delay, which is not a classic feature of ROHHAD syndrome. HIDEA syndrome presents similarities with ROHHAD, including hypoventilation, obesity, and dysautonomia. To date, only 14% of endocrinological disturbances have been reported in HIDEA patients. Better delineation of both syndromes is required to investigate the eventual involvement of P4HTM, a regulator of calcium dynamics and gliotransmission, in ROHHAD patients. Conclusion: In the case of clinical evidence of ROHHAD in a child with abnormal neurological development or eye abnormalities, we suggest that the P4HTM gene be systematically interrogated in addition to the analysis of the PHOX2B gene. A better delineation of the natural history of HIDEA is required to allow further comparisons between features of HIDEA and ROHHAD. The clinical similarities could potentially orient some molecular hypotheses in the field of ROHHAD research.
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Project description:BackgroundThe autoimmune regulator (AIRE) gene influences thymic self-tolerance induction. In autoimmune polyendocrinopathy syndrome type 1 (APS1; OMIM 240300), recessive AIRE mutations lead to autoimmunity targetting endocrine and other epithelial tissues, although chronic candidiasis usually appears first. Autoimmunity and chronic candidiasis can associate with thymomas as well. Patients with these tumours frequently also have high titre immunoglobulin G autoantibodies neutralising type I interferon (IFN)-alpha and IFN-omega, which are secreted signalling proteins of the cytokine superfamily involved in both innate and adaptive immunity.Methods and findingsWe tested for serum autoantibodies to type I IFNs and other immunoregulatory cytokines using specific binding and neutralisation assays. Unexpectedly, in 60/60 Finnish and 16/16 Norwegian APS1 patients with both AIRE alleles mutated, we found high titre neutralising immunoglobulin G autoantibodies to most IFN-alpha subtypes and especially IFN-omega (60% homologous to IFN-alpha)-mostly in the earliest samples. We found lower titres against IFN-beta (30% homologous to IFN-alpha) in 23% of patients; two-thirds of these (from Finland only) also had low titres against the distantly related "type III IFN" (IFN-lambda1; alias interleukin-29). However, autoantibodies to the unrelated type II IFN, IFN-gamma, and other immunoregulatory cytokines, such as interleukin-10 and interleukin-12, were much rarer and did not neutralise. Neutralising titres against type I IFNs averaged even higher in patients with APS1 than in patients with thymomas. Anti-type I IFN autoantibodies preceded overt candidiasis (and several of the autoimmune disorders) in the informative patients, and persisted for decades thereafter. They were undetectable in unaffected heterozygous relatives of APS1 probands (except for low titres against IFN-lambda1), in APS2 patients, and in isolated cases of the endocrine diseases most typical of APS1, so they appear to be APS1-specific. Looking for potentially autoimmunising cell types, we found numerous IFN-alpha(+) antigen-presenting cells-plus strong evidence of local IFN secretion-in the normal thymic medulla (where AIRE expression is strongest), and also in normal germinal centres, where it could perpetuate these autoantibody responses once initiated. IFN-alpha2 and IFN-alpha8 transcripts were also more abundant in antigen-presenting cells cultured from an APS1 patient's blood than from age-matched healthy controls.ConclusionsThese apparently spontaneous autoantibody responses to IFNs, particularly IFN-alpha and IFN-omega, segregate like a recessive trait; their high "penetrance" is especially remarkable for such a variable condition. Their apparent restriction to APS1 patients implies practical value in the clinic, e.g., in diagnosing unusual or prodromal AIRE-mutant patients with only single components of APS1, and possibly in prognosis if they prove to predict its onset. These autoantibody responses also raise numerous questions, e.g., about the rarity of other infections in APS1. Moreover, there must also be clues to autoimmunising mechanisms/cell types in the hierarchy of preferences for IFN-omega, IFN-alpha8, IFN-alpha2, and IFN-beta and IFN-lambda1.
| S-EPMC1475653 | biostudies-literature
Project description:BackgroundROHHAD syndrome (Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation) is rare. Rapid-onset morbid obesity is usually the first recognizable sign of this syndrome, however a subset of patients develop ROHHAD syndrome without obesity. The prevalence of this entity is currently unknown. Alteration of respiratory control as well as dysautonomic disorders often have a fatal outcome, thus early recognition of this syndrome is essential.Material and methodsA retrospective, observational, multicenter study including all cases of ROHHAD without rapid-onset obesity diagnosed in France from 2000 to 2020.ResultsFour patients were identified. Median age at diagnosis was 8 years 10 months. Median body mass index was 17.4 kg/m2. Signs of autonomic dysfunction presented first, followed by hypothalamic disorders. All four patients had sleep apnea syndrome. Hypoventilation led to the diagnosis. Three of the four children received ventilatory support, all four received hormone replacement therapy, and two received psychotropic treatment. One child in our cohort died at 2 years 10 months old. For the three surviving patients, median duration of follow-up was 7.4 years.ConclusionROHHAD syndrome without rapid-onset obesity is a particular entity, appearing later than ROHHAD with obesity. This entity should be considered in the presence of dysautonomia disorders without brain damage. Likewise, the occurrence of a hypothalamic syndrome with no identified etiology requires a sleep study to search for apnea and hypoventilation. The identification of ROHHAD syndrome without rapid-onset obesity is a clinical challenge, with major implications for patient prognosis.
| S-EPMC9471950 | biostudies-literature
Project description:BackgroundRapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a very rare and potentially fatal pediatric disorder, the cause of which is presently unknown. ROHHAD is often compared to Prader-Willi syndrome (PWS) because both share childhood obesity as one of their most prominent and recognizable signs, and because other symptoms such as hypoventilation and autonomic dysfunction are seen in both. These phenotypic similarities suggest they might be etiologically related conditions. We performed an in-depth clinical comparison of the phenotypes of ROHHAD and PWS and used NGS and Sanger sequencing to analyze the coding regions of genes in the PWS region among seven ROHHAD probands.ResultsDetailed clinical comparison of ROHHAD and PWS patients revealed many important differences between the phenotypes. In particular, we highlight the fact that the areas of apparent overlap (childhood-onset obesity, hypoventilation, autonomic dysfunction) actually differ in fundamental ways, including different forms and severity of hypoventilation, different rates of obesity onset, and different manifestations of autonomic dysfunction. We did not detect any disease-causing mutations within PWS candidate genes in ROHHAD probands.ConclusionsROHHAD and PWS are clinically distinct conditions, and do not share a genetic etiology. Our detailed clinical comparison and genetic analyses should assist physicians in timely distinction between the two disorders in obese children. Of particular importance, ROHHAD patients will have had a normal and healthy first year of life; something that is never seen in infants with PWS.
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Project description:ObjectiveRapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) is rare, and manifestations of autonomic dysregulation are diverse and may be overlooked. We aimed to evaluate the incidence of these manifestations.MethodsPatients with ROHHAD syndrome reported before and after 2019 were divided into groups 1 and 2. Patients who were diagnosed at three regional hospitals in China were included in group 3. We collected the age of each specific term of the ROHHAD (neurogenic tumor, NET) acronym and the detailed manifestations of each term, and compared them among the three groups.ResultsA total of 16 patients were diagnosed within the 2-year period. Two had neurogenic tumors and cognitive and behavioral abnormalities before developing rapid obesity. At least 93.8% of the patients had ≥ 4 symptoms of autonomic dysregulation. When comparing autonomic dysregulation among groups 1-3, the rates of cardiovascular manifestations were NA vs 12.8% vs 81.2%; gastrointestinal disturbances were 11.4% vs 8.5% vs 62.5%; strabismus was 25.7% vs 12.8% vs 62.5%; sleep disturbance was NA vs 6.4% vs 50.0%; and abnormal pain threshold was NA vs 10.6% vs 25.0% (all P < 0.05). The rates of cognitive and behavioral abnormalities were NA vs 29.8% and 87.5% (P < 0.01).ConclusionRapid-onset obesity is not always the first sign of ROHHAD syndrome. Higher rates of autonomic dysregulation and cognitive and behavioral abnormalities with multiple manifestations of autonomic dysregulation coexisted in our cohort, indicating that evaluations of autonomic function and the limbic system should be strengthened when assessing this condition.
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