Allgrove syndrome: case report of 7 years old boy from Bahawalpur.

Allgrove syndrome is a rare autosomal recessive syndrome of unknown prevalence. The first case of Allgrove syndrome was reported in 1978 by Allgrove. It is characterized by triad of achalasia, alacrima and adrenal hypoplasia. There are also associated autonomic and neurological manifestations. We report the case of a 7 years old boy being treated for achalasia cardia, presented with fits and altered sensorium which on further investigations was found to be due to adrenal insensitivity (Raised ACTH level, low Cortisol level, and normal Aldosterone and Renin ratio). He also had undiagnosed alacrima since birth, mild degree of hearing loss and autonomic instability in the form of episodic hypertension.

Long-term clinical follow-up and molecular genetic findings in eight patients with triple A syndrome.

UNLABELLED: The triple A syndrome (Allgrove syndrome, OMIM #231550) is caused by autosomal recessively inherited mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN. This multisystemic disease is characterised by achalasia, alacrima, adrenal insufficiency and neurological impairment. We analyse long-term clinical follow-up and results of sequencing of the AAAS gene in eight patients with triple A syndrome aged from 2 to 35 years. At the time of diagnosis, all patients presented with alacrima, neurological dysfunction, dermatological abnormalities, seven of them with adrenal insufficiency and five of them with achalasia. Sequencing of the AAAS gene identified the p.S263P mutation in five of eight patients, supporting the hypothesis that this mutation is a founder mutation in Slavic population. One of the patients is homozygous for the p.S263P mutation, two are compound heterozygous for the p.S263P and the p.G14fs mutation, two are compound heterozygous for the p.S263Pro mutation and p.S296Y mutation, two are compound heterozygous for the p.G14fs and the p.Q387X mutations and one is homozygous for the p.Q387X mutation. In the course of the follow-up time of 4-29 years, progression of existing and appearance of new symptoms developed. Although severe, many of these symptoms presented in all six young adult patients are often overlooked or neglected: postural hypotension with blurred vision and syncope, hyposalivation resulting with complete edentulosis, talocrular contractures with permanent walking difficulties and erectile dysfunction in male patients. Triple A syndrome is a progressive debilitating disorder which may seriously affect quality of life and even be life-threatening in patients with severe neurological impairment. CONCLUSION: Long-term follow-up of patients with triple A syndrome revealed a variety of the clinical features involving many systems. Progressive natural course of the disease may seriously affect quality of life and even be life-threatening in patients with severe neurological impairment.

Triosephosphate isomerase, carbonic anhydrase, and creatinine kinase-brain isoform are possible antigen targets in patients with achalasia.

BACKGROUND: Idiopathic achalasia is an uncommon esophageal motor disorder. The disease involves interaction between inflammatory and autoimmune responses. However, the antigens related to the disease are still unknown. AIM: To identify the possible antigen targets in muscle biopsies from lower esophageal sphincter (LES) of achalasia patients. METHODS: Esophageal biopsies of patients with type I and type II achalasia and esophagogastric junction outflow obstruction (EGJOO) were analyzed. Lower esophageal sphincter muscle biopsy from a Healthy organ Donor (HD) was included as control for two-dimensional gel electrophoresis. Immunoblotting of muscle from LES lysate with sera of type I, type II achalasia, or type III achalasia, sera of EGJOO and sera of healthy subjects (HS) was performed. The target proteins of the serum were identified by mass spectrometry Matrix-assited laser desorption/ionization time-of-flight (MALDI-TOF). KEY RESULTS: The proteomic map of muscle from LES tissue lysates of type I, and type II achalasia, EGJOO, and HD were analyzed and divided into three important regions. We found a difference in the concentration of certain spots. Further, we observed the serum reactivity of type I achalasia and type II achalasia against 45 and 25 kDa bands of type I achalasia tissue. Serum of type III achalasia and EGJOO mainly recognized 25 kDa band. Bands correspond to triosephosphate isomerase (TPI) (25 kDa), carbonic anhydrase (CA) (25 kDa) and creatinine kinase-brain (CKB) isoform (45 kDa). CONCLUSIONS AND INFERENCES: We identify three antigen targets, TPI, CA, and CKB isoform, which are recognized by sera from patients with achalasia.

Multiplex immunoassays reveal increased serum cytokines and chemokines associated with the subtypes of achalasia.

BACKGROUND: Achalasia is an esophageal motility disorder with unknown etiology. Previous findings indicate that immune-mediated inflammatory process causes inhibitory neuronal degeneration. This study was designed to evaluate levels of serological cytokines and chemokines in patients with achalasia. METHODS: We collected information from forty-seven patients with achalasia who underwent peroral endoscopic myotomy. Control samples were collected from forty-seven age- and sex-matched healthy people. The concentrations of serological cytokines and chemokines were analyzed by Luminex xMAP immunoassay. Serological and clinical data were compared between groups. KEY RESULTS: Compared with healthy controls, achalasia patients had significantly increased concentrations of eleven cytokines and chemokines, namely, TGF-ß1 (P < .001), TGF-ß2 (P < .001), TGF-ß3 (P < .001), IL-1ra (P < .001), IL-17 (P = .005), IL-18 (P < .001), IFN-γ (P < .001), MIG (P < .001), PDGF-BB (P < .001), IP-10 (P = .003), and SCGF-B (P < .001). Gene ontology (GO) and network functional enrichment analysis revealed regulation of signaling receptor activity and receptor-ligand activity were the most related pathways of these cytokines and chemokines. Levels of twelve cytokines and chemokines were significantly increased in type III compared with I/II achalasia, namely, TGF-ß2, IL-1ra, IL-2Ra, IL-18, MIG, IFN-γ, SDF-1a, Eotaxin, PDGF-BB, IP-10, MCP-1, and TRAIL. CONCLUSIONS AND INFERENCES: Patients with achalasia exhibited increased levels of serological cytokines and chemokines. Levels of cytokines and chemokines were significantly increased in type III than in type I/II achalasia. Cytokines and chemokines might contribute to the inflammatory development of achalasia.

Hematological indices as indicators of silent inflammation in achalasia patients: A cross-sectional study.

Complete blood count (CBC)-derived parameters such as neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), eosinophil-to-lymphocyte (ELR) ratio, and platelet-to-lymphocyte ratio (PLR) are sensitive markers of occult inflammation and disease activity for systemic lupus erythematosus, rheumatoid arthritis, psoriasis, esophageal cancer, etc. We assessed NLR, PLR, MLR, and ELR as indicators of inflammation in achalasia patients.This cross-sectional study included 103 achalasia patients and 500 healthy blood donor volunteers (HD). Demographic, clinical and laboratory information was collected. NLR, MLR, ELR and PLR were calculated. Peripheral Th22, Th17, Th2 and Th1 subsets were determined by flow cytometry. Correlation between hematologic indices and clinical questionnaires scores, HRM parameters and CD4+ T-cells were assessed. Hematologic parameters associated with the different achalasia subtypes were evaluated by logistic regression analysis.Hemoglobin, leukocytes, lymphocytes, monocytes, and platelets counts were significantly lower in achalasia patients vs controls. NLR (P = .006) and ELR (P < .05) were higher in achalasia patients vs controls. NLR was significantly associated with achalasia in multivariate analysis (P < .001). Compared to HD, the achalasia group was 1.804 times more likely to have higher NLR (95% CI 1.287-2.59; P < .001). GERD-HRQL score had statistically significant correlations with PLR (Pearson's rho:0.318, P = .003), and ELR (Pearson's rho:0.216; P = .044). No correlation between CD4+ T-cells and hematologic indices were determined. NLR with a cut-off value of ≥2.20 and area under the curve of 0.581 yielded a specificity of 80% and sensitivity of 40%, for the diagnosis of achalasia.NLR is increased in achalasia patients vs HD. Sensitivity and specificity achieved by NLR may contribute to a clinical and manometric evaluation. We suggest these indices as potential indicators of silent inflammation and disease activity.

Expression and significance of interleukin-17 and interleukin-22 in the serum and the lower esophageal sphincter of patients with achalasia.

Background/Aim: : We studied the expression of interleukin-17 and interleukin-22 in the serum and the lower esophageal sphincter (LES) in healthy individuals and in patients diagnosed with achalasia (AC) to gain a better understanding of the etiopathogenesis of AC. Patients and Methods: Our study comprised 14 randomly selected patients with AC who underwent peroral endoscopic myotomy and 14 randomly selected healthy individuals who served as controls. Venous blood samples were evaluated in all study subjects to detect the expression of interleukin-17 and interleukin-22 in the serum using an enzyme-linked immunosorbent assay. Immunohistochemistry studies were performed to evaluate LES myofilaments obtained from both groups, as well as from 12 patients diagnosed with a subendothelial non-invasive tumor and who had undergone submucosal tunneling endoscopic resection, to assess the expression of interleukin-17 and interleukin-22 in LES myofilaments. Results: Compared with that in the control group, the expression of interleukin-17 and interleukin-22 in the serum and LES, in patients with AC, was significantly increased and was positively correlated. Conclusion: Interleukin-17 and interleukin-22 are upregulated in the serum and LES in patients with AC, suggesting that both interleukin-17 and interleukin-22 are involved in the pathogenesis of AC, and that AC may be an immune-mediated inflammatory disease.

Triple A Syndrome: Preliminary Response to the Antioxidant N-Acetylcysteine Treatment in a Child.

INTRODUCTION: Triple A syndrome (AAAS) is a rare autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency, autonomic dysfunction, and progressive neurodegeneration. Increased oxidative stress, demonstrated in patients' fibroblasts in vitro, may be a central disease mechanism. N-acetylcysteine protects renal function in patients with kidney injuries associated with increased oxidative stress and improves viability of AAAS-knockdown adrenal cells in vitro. PATIENT AND RESULTS: A boy diagnosed with AAAS presented with short stature and increased oxidative stress in vivo assessed by increased thiobarbituric acid reactive substances (TBARS), which are markers of lipid peroxidation, and by the susceptibility of LDL to oxidation and the capacity of HDL to prevent it. A homozygous missense germline mutation (c.523G>T, p.Val175Phe) in AAAS was identified. N-acetylcysteine (600 mg orally, twice daily) decreased oxidative stress but did not change the patient's growth pattern. CONCLUSIONS: An increase in oxidative stress is reported for the first time in vivo in an AAAS patient. N-acetylcysteine was capable of decreasing TBARS levels, reducing the susceptibility of LDL to oxidation and improving the antioxidant role of HDL. The long-term effect of antioxidant treatment should be evaluated to determine the real benefit for the prevention of the degenerative process in AAAS.

Poorly Controlled Congenital Hypothyroidism due to an Underlying Allgrove Syndrome.

BACKGROUND: Congenital hypothyroidism of thyroidal origin (CHT) is a common disorder in pediatric endocrinology practices, which can be difficult to manage. Elevated thyrotropin (TSH) concentrations are in the great majority of cases explained by poor compliance to levothyroxine therapy. METHODS: Case description. RESULTS: We present a boy with CHT, with 2 heterozygous mutations in the TSH receptor gene, who showed persistently elevated TSH concentrations and psychomotor retardation, initially misinterpreted as malcompliance. At the age of 4 years, he was diagnosed with adrenal insufficiency, wherefore a broad diagnostic search was initiated. After the start of glucocorticoid replacement therapy, his TSH normalized and the levothyroxine could be lowered. At the age of 6 years, his TSH increased again, this time caused by malabsorption of levothyroxine due to esophageal achalasia. In retrospect, alacrima was also present and the diagnosis of Allgrove syndrome was genetically confirmed. The CHT was considered a separate disease entity. CONCLUSIONS: In case of persistently elevated TSH levels in children with CHT, causes other than noncompliance must be considered. Second, in establishing the cause of adrenal insufficiency, specific symptoms, such as alacrima, are easily overlooked. Third, Allgrove syndrome is a rare disorder, in which diagnostic delay can lead to potentially life-threatening complications.

Allgrove Syndrome: Adrenal Insufficiency with Hypertensive Encephalopathy.

Allgrove syndrome or triple-Asyndrome is a rare familial multisystem autosomal recessive disorder. It is characterised by triad of alacrima, achalasia and adrenal insufficiency due to adrenocorticotropin hormone (ACTH) resistance. If it is associated with autonomic dysfunction, it is termed as 4-Asyndrome. This syndrome is caused by a mutation in the Achalasia - Addisonism - Alacrima (AAAS) gene on chromosome 12q13 encoding the nuclear pore protein ALADIN. A5-year boy presented with history of fits and altered sensorium for one day. He also had increased pigmentation of body and persistent vomiting since six months of age. Laboratory investigations and imaging revealed alacrimia, achalasia and adrenal insufficiency due to ACTH resistance. He had episodes of hypertensive crises, for which he was thoroughly investigated and it was found to be due to autonomic instability. Based on clinical findings and investigations he was diagnosed as case of Allgrove syndrome or 4-Asyndrome with autonomic dysfunction.

Megaoesophagus in rats: a clinical, pathological and morphometrical study.

Megaoesophagus was observed in 82 Long-Evans rats aged 3-32 months. Clinically, the hair was coarse, the neck distended, the mouth opened, wetted by saliva and soiled by bedding material, and the respiration characterized by tachypnoea and inspiratory crackles. By radiography, after barium administration, the oesophagus was seen to be dilated and filled with impacted dry food in the precardial region. The size of the dilatation varied depending on the oesophageal region and reached a diameter of 12 mm in the most severe case. Histologically, the muscular layers of the dilated portions showed focal inflammation and single fibre necrosis. Each affected oesophagus had (1) an increased circumference and radius and a reduced number of myenteric ganglion cells in both the thoracic and abdominal portions, and (2) a decreased thickness of the muscular layers in the thoracic portion and at the level of the cardia. A simple geometrical model showed that the reduced ganglion cell number was not due to a change in shape of the dilated oesophagus. Since no sign of infectious disease was found in these animals, and rats of other strains kept at the same time under the same conditions were not affected, a hereditary aetiology is suggested.

Megaesophagus in nine ferrets.

Megaesophagus was diagnosed in 9 adult ferrets. Clinical history of the ferrets included regurgitation, difficulty in swallowing, partial anorexia, and lethargy. Cachexia, dehydration, weakness, and ptyalism were observed on physical examination. Radiography revealed the esophagus of each ferret to be dilated in the thoracic and cervical regions. Of 4 ferrets that had lymphocytopenia, 2 had concurrent leukopenia. Serum biochemical analysis revealed high activity of alanine transaminase (4 ferrets) and aspartate transaminase (3), and hypoglycemia (4). Treatment included administration of fluid, antibiotics, and agents directed against possible primary causes of megaesophagus. Treatments were ineffective, and all of the ferrets died or were euthanatized. All 6 ferrets that were submitted for necropsy had bronchopneumonia, hepatic lipidosis, mild esophagitis, and gastritis. The etiopathogenesis of megaesophagus in the ferrets was not determined.

[Regulation of the functional status of the lower esophageal sphincter with gastrointestinal hormones in cardiospasm and reflux esophagitis]. / Patofiziologicheskie aspekty reguliatsii funktsional'nogo sostoianiia nizhnego pishchevodnogo sfinktera gastrointestinal'nymi gormonami pri kardiospazme i refliuks-ézofagite.

A role of gastrointestinal hormones in the regulation of the lower esophageal sphincter was studied in 22 patients with cardiospasm and 21 with reflux esophagitis. The levels of gastrin, vasoactive intestinal polypeptide (VIP), glucagon, insulin, and c peptide were determined by radioactive assay before and after surgical treatment. In opposite abnormalities (cardiospasm and reflux esophagitis), there is a different degree of VIP secretion both at the beginning and after functional exercises. Before and after functional exercises, the level of VIP was higher than in those with cardiospasm. The value of VIP on fasting and after functional exercises may be an additional information to establish the diagnoses of cardiospasm and reflux esophagitis and to evaluate the efficiency of the treatment performed.

Allgrove syndrome.

Allgrove syndrome is a rare autosomal recessive disorder. It is also known as the 3A syndrome and characterised by the triad of achalasia, alacrima and adrenal insufficiency. The AAAS gene is encoded on chromosome 12q13. We report the case of a 23-year-old woman who presented at the hospital with adrenal crisis that was triggered by infection of the urinary system and gastrointestinal bleeding. She had a known diagnosis of achalasia for eight years, and ophthalmologic examination revealed alacrima. Based on our findings, the patient was diagnosed with Allgrove syndrome.

[Preoperative and postoperative nutritional evaluation in patients with non-advanced megaesophagus]. / Avaliação nutricional pré e pós-operatória em pacientes com megaesôfago não-avançado.

UNLABELLED: Megaesophagus, an affection characterized by the aperistalsis of the esophageal body and deficient relaxation of the lower esophageal sphincter presents dysphagia as the most frequent complaint. The goal of this study was to evaluate the nutritional status of patients with non-advanced megaesophagus in pre and postoperative periods of laparoscopic cardiomyotomy. Ten patients were studied in five moments (pre operative and at 1, 3, 6 and 12 months after surgery). The anthropometric, hematimetric and biochemical parameters were studied in five moments. CONCLUSIONS: 1) most patients with non-advanced megaesophagus were eutrophic; 2) surgical treatment led to improvement in nutritional status and increase of HDL cholesterol fraction.