HGNC.SYMBOL:NFKB1 Haploinsufficiency

[PMID:26279205] [SUPPORT] we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency. --- Explanation: Identifies NFKB1 haploinsufficiency as a cause of CVID through degradation of the altered protein with loss of p50 transcription factor.

[PMID:29477724] [SUPPORT] Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans. --- Explanation: Large-scale study confirming NFKB1 as the most common monogenic cause of CVID in European populations.


HGNC.SYMBOL:CTLA4 Haploinsufficiency

[PMID:25213377] [SUPPORT] We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. --- Explanation: Identifies CTLA4 haploinsufficiency as a cause of CVID-like immune dysregulation with hypogammaglobulinemia, autoimmune cytopenias, and lymphocytic organ infiltration.


HGNC.SYMBOL:BAFF-R (TNFRSF13C) Mutations


MONDO:0037251

[PMID:36908126] [SUPPORT] Splenomegaly is associated with a poor prognosis in cirrhosis and is caused by spleen congestion and by enlargement and hyperactivation of splenic lymphoid tissue. --- Explanation: Establishes splenomegaly as a hallmark feature of portal hypertension with prognostic significance.

[PMID:32408299] [SUPPORT] After food ingestion, the spleen responds either with contraction according to a vasomotor reaction or postprandial congestion with significant increases in volume. The spleen's rhythmical function is lost in the clinical picture of portal hypertension --- Explanation: Demonstrates that splenomegaly in portal hypertension involves loss of normal rhythmic splenic contraction, contributing to persistent enlargement.


MONDO:0037251

[PMID:27860293] [SUPPORT] Thrombocytopenia is a common haematological disorder in patients with chronic liver disease. It is multifactorial and severity of liver disease is the most influential factor. --- Explanation: Confirms thrombocytopenia as a common and multifactorial complication in the setting of chronic liver disease and portal hypertension.

[PMID:41306370] [SUPPORT] Thrombocytopenia is a prevalent condition in patients with chronic liver disease and portal hypertension. Multiple mechanisms related to increased platelet destruction or decreased platelet production contribute to thrombocytopenia. --- Explanation: Recent review confirming the high prevalence of thrombocytopenia in portal hypertension and its multifactorial pathogenesis.


MONDO:0037251

[DOI:10.3390/gastroent14030024] [SUPPORT] About 75% of patients with advanced chronic liver disease experience anemia. The causes of anemia are complex and multifactorial, particularly in cirrhotic patients. Acute and long-term blood loss from the upper gastrointestinal tract, malnutrition, an enlarged spleen brought on by portal hypertension, hemolysis, and coagulation issues are the main causes of anemia. --- Explanation: Establishes the high prevalence of anemia in chronic liver disease and identifies splenomegaly from portal hypertension as one of the key contributing factors.


MONDO:0037251

[PMID:27860293] [SUPPORT] portal hypertension causes pooling and sequestration of all corpuscular elements of the blood, predominantly thrombocytes, in the enlarged and congested spleen. --- Explanation: Confirms that hypersplenism causes sequestration of all blood cell elements including leukocytes, not just platelets.


MONDO:0037251

[PMID:27860293] [SUPPORT] portal hypertension causes pooling and sequestration of all corpuscular elements of the blood, predominantly thrombocytes, in the enlarged and congested spleen. --- Explanation: Hypersplenism causes sequestration of all blood cell lines, which when severe leads to pancytopenia.


MONDO:0037251

[PMID:28535799] [SUPPORT] In chronic liver diseases, splenomegaly and hypersplenism can manifest following the development of portal hypertension. --- Explanation: Splenomegaly from portal hypertension causes capsule distension leading to left upper quadrant pain and discomfort.


MONDO:0037251

[PMID:36908126] [SUPPORT] Splenomegaly is associated with a poor prognosis in cirrhosis and is caused by spleen congestion and by enlargement and hyperactivation of splenic lymphoid tissue. --- Explanation: Significant splenomegaly from portal hypertension can compress adjacent structures including the stomach, causing early satiety.


MONDO:0037251

[DOI:10.3390/gastroent14030024] [SUPPORT] About 75% of patients with advanced chronic liver disease experience anemia. The causes of anemia are complex and multifactorial, particularly in cirrhotic patients. --- Explanation: Fatigue in congestive splenomegaly is primarily driven by the high prevalence of anemia in chronic liver disease and its multifactorial causes including splenic sequestration.


MONDO:0037251

[PMID:24679494] [SUPPORT] Hyperdynamic circulatory syndrome develops, leading to esophageal varices or ascites. --- Explanation: Portal hypertension drives collateral vessel formation and esophageal varices, which can cause gastrointestinal hemorrhage.


MONDO:0037251

[PMID:36908126] [INDIRECT EVIDENCE] [SUPPORT] As liver disease progresses, intrahepatic vascular resistance increases (backward flow theory of portal hypertension) and collateral veins develop. Adequate portal hypertension is required to maintain portal flow into the liver through an increase in blood flow into the portal venous system (forward flow theory of portal hypertension). The splenic artery resistance index is significantly and selectively elevated in cirrhotic patients. In portal hypertension, a local hyperdynamic state occurs around the spleen. --- Explanation: This review establishes the hemodynamic basis of congestive splenomegaly through the backward and forward flow theories of portal hypertension and the selective elevation of splenic artery resistance.

[PMID:24679494] [INDIRECT EVIDENCE] [SUPPORT] Portal hypertension is a major complication of liver disease that results from a variety of pathologic conditions that increase the resistance to the portal blood flow into the liver. As portal hypertension develops, the formation of collateral vessels and arterial vasodilation progresses, which results in increased blood flow to the portal circulation. --- Explanation: This review explains that increased intrahepatic resistance combined with splanchnic vasodilation and increased portal blood flow drives portal hypertension and consequent splenic congestion.

[PMID:11926560] [INDIRECT EVIDENCE] [SUPPORT] The increase in spleen size is followed by an increase in splenic blood flow, which participates in portal hypertension actively congesting the portal system. --- Explanation: Demonstrates that splenomegaly itself contributes to portal hypertension through increased splenic blood flow, creating a positive feedback loop of congestion.


MONDO:0037251


MONDO:0037251

[PMID:8170720] [INDIRECT EVIDENCE] [SUPPORT] In course of experimental pre-hepatic portal hypertension in the rat, the most important histological alterations in the spleen, are represented by pooling of blood in the red pulp, activation of the macrophagic system, with hyperplasia of the histiocytes, increase of reticular fibers and of subcapsular myo-fibroblasts, and finally by evolution towards a diffuse fibrosis all over the parenchyma. --- Explanation: This experimental model of congestive splenomegaly directly demonstrates the sequence of pathological changes from red pulp congestion through macrophage activation to diffuse fibrosis.

[PMID:32945524] [INDIRECT EVIDENCE] [SUPPORT] In addition to splenic sinus congestion, diffuse fibrosis was detected in the splenic cords in the red pulp of patients with PH. The degree of the fibrosis was well correlated with severity in thrombocytopenia and splenomegaly. --- Explanation: Human histological study confirming that splenic fibrosis in portal hypertension progresses in the red pulp and directly correlates with clinical severity of cytopenias and spleen size.

[PMID:32945524] [INDIRECT EVIDENCE] [SUPPORT] Cells expressing α-smooth muscle actin dramatically increased in the splenic cord. Cytoglobin (Cygb) expression was detected in human splenic cords as reported in animal reticular cells, and fluorescent double immunostaining revealed that these cells expressed α-smooth muscle actin in patients with PH, suggesting transformation of Cygb-expressing cells to myofibroblastic cells. --- Explanation: Identifies the cellular mechanism of splenic fibrosis through myofibroblastic transformation of cytoglobin-expressing cells in the splenic cords.

[PMID:11926560] [INDIRECT EVIDENCE] [SUPPORT] In this condition, splenomegaly is not only caused by portal congestion, but it is mainly due to tissue hyperplasia and fibrosis. --- Explanation: Establishes that congestive splenomegaly involves active tissue remodeling (hyperplasia and fibrosis) beyond passive venous congestion.


MONDO:0037251

[PMID:36908126] [INDIRECT EVIDENCE] [SUPPORT] Splenomegaly is associated with a poor prognosis in cirrhosis and is caused by spleen congestion and by enlargement and hyperactivation of splenic lymphoid tissue. Hypersplenism can lead to thrombocytopenia caused by increased sequestering and breakdown of platelets in the spleen. --- Explanation: Directly establishes the mechanism of hypersplenism in congestive splenomegaly with platelet sequestration and destruction.

[PMID:27860293] [INDIRECT EVIDENCE] [SUPPORT] The pathophysiology of thrombocytopenia in chronic liver disease has long been associated with the hypothesis of hypersplenism, where portal hypertension causes pooling and sequestration of all corpuscular elements of the blood, predominantly thrombocytes, in the enlarged and congested spleen. --- Explanation: Describes the classic hypersplenism mechanism affecting all blood cell lines, with platelets being predominantly affected.

[PMID:27860293] [INDIRECT EVIDENCE] [SUPPORT] Thrombopoietin is predominantly produced by the liver and is reduced when liver cell mass is severely damaged. This leads to reduced thrombopoiesis in the bone marrow and consequently to thrombocytopenia in the peripheral blood of patients with advanced-stage liver disease. --- Explanation: Identifies the additional mechanism of decreased hepatic thrombopoietin production contributing to thrombocytopenia beyond splenic sequestration.

[PMID:41306370] [INDIRECT EVIDENCE] [SUPPORT] Increased platelet destruction occurs due to splenic sequestration caused by hypersplenism or immune-mediated conditions. Decreased platelet production results from a decline in thrombopoietin production, bone marrow suppression by medications, or toxic insults. --- Explanation: Recent comprehensive review confirming the dual mechanism of both increased platelet destruction (hypersplenism) and decreased production (reduced thrombopoietin) in portal hypertension.


MAXO:0000058

[PMID:41306370] [SUPPORT] Persistent liver injury halts the regenerative capacity of hepatocytes and activates mechanisms that result in the replacement of normal hepatic parenchyma with extracellular matrix deposits. As liver fibrosis develops, the liver undergoes architectural changes and alterations in microcirculation that lead to increased intrahepatic vascular resistance and portal hypertension. --- Explanation: Addressing the underlying cause of liver injury is essential because persistent hepatic damage drives fibrosis and portal hypertension, which in turn causes congestive splenomegaly.


MAXO:0000187

[PMID:41306370] [SUPPORT] Nonselective beta-blockers are the cornerstone of long-term management for clinically significant portal hypertension. --- Explanation: Establishes non-selective beta blockers as the standard pharmacological treatment for clinically significant portal hypertension.


MAXO:0001077

[PMID:28535799] [SUPPORT] We conclude with a discussion of the possible therapeutic strategies for modulating splenic abnormalities, including the novel potential usage of nanomedicine in non-surgically targetting splenic disorders for the treatment of liver cirrhosis. --- Explanation: This review discusses splenectomy and other therapeutic strategies for managing splenic abnormalities in the context of liver cirrhosis and portal hypertension.


MAXO:0001515

[PMID:27860293] [PARTIAL] insufficient platelet recovery after relief of portal hypertension by shunt procedures or minor and transient recovery after splenic artery embolization have caused many to question the importance and relative contribution of this mechanism to thrombocytopenia. --- Explanation: Notes that splenic artery embolization produces only minor and transient platelet recovery, suggesting that hypersplenism is not the sole mechanism of thrombocytopenia and that embolization has limited efficacy.


MAXO:0001515

[PMID:41306370] [SUPPORT] Indications for transjugular intrahepatic portosystemic shunt placement include failure to control portal hypertension-related bleeding, early rebleeding, and refractory or recurrent ascites. --- Explanation: Establishes the clinical indications for TIPS in the management of portal hypertension complications.


MONDO:0005480

[PMID:25102574] [SUPPORT] The two most common variants are irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD). --- Explanation: This supports the broad clinical entity of contact dermatitis comprising allergic and irritant forms.


MONDO:0005480

[PMID:39941494] [SUPPORT] Background/Objectives: Eyelid dermatitis is an inflammatory disease affecting the palpebral skin characterized by itching, edema, and scaling of the periorbital area. --- Explanation: This human clinical series supports itching as a characteristic manifestation of contact dermatitis.


MONDO:0005480

[PMID:9590995] [SUPPORT] Clinical signs include vesicles, papules, bullae, erythema, edema, scaling, and lichenification. --- Explanation: This review supports erythema as a common clinical sign of contact dermatitis, particularly irritant presentations.


MONDO:0005480

[PMID:39941494] [SUPPORT] Background/Objectives: Eyelid dermatitis is an inflammatory disease affecting the palpebral skin characterized by itching, edema, and scaling of the periorbital area. --- Explanation: This human clinical study supports scaling as a characteristic manifestation of contact dermatitis.


MONDO:0005480

[PMID:25274939] [INDIRECT EVIDENCE] [SUPPORT] involves skin barrier disruption --- Explanation: This identifies barrier disruption as a distinct mechanistic step in irritant contact dermatitis.


MONDO:0005480

[PMID:25274939] [INDIRECT EVIDENCE] [SUPPORT] involves skin barrier disruption, cellular changes, and release of proinflammatory mediators. --- Explanation: This supports proinflammatory mediator release as a distinct ICD mechanism.

[DOI:10.1155/2013/916497] [INDIRECT EVIDENCE] [SUPPORT] Irritant contact dermatitis is a result of activated innate immune response to various external stimuli and consists of complex interplay which involves skin barrier disruption, cellular changes, and release of proinflammatory mediators. --- Explanation: This corroborates activated innate immune signaling and mediator release as central mechanisms in irritant contact dermatitis.


MONDO:0005480


MONDO:0005480

[PMID:25274939] [INDIRECT EVIDENCE] [SUPPORT] release of proinflammatory mediators that directly recruit and activate T lymphocytes. --- Explanation: This supports recruitment and activation of inflammatory cells as a separate downstream ICD mechanism.


MONDO:0005480

[PMID:19839974] [INDIRECT EVIDENCE] [SUPPORT] Recent advances in the pathophysiology of ACD have demonstrated the important role of skin innate immunity in the sensitization process --- Explanation: This supports skin innate immune activation as a distinct mechanistic stage in allergic contact dermatitis sensitization.


MONDO:0005480

[PMID:19839974] [INDIRECT EVIDENCE] [SUPPORT] Subsets of CD4+ T cells endowed with suppressive activity are responsible for both the down-regulation of eczema in allergic patients and the prevention of priming to haptens in nonallergic individuals. --- Explanation: This review identifies suppressive CD4-positive regulatory T-cell activity as a core counter-regulatory axis in allergic contact dermatitis.


MONDO:0005480

[PMID:19839974] [INDIRECT EVIDENCE] [SUPPORT] Allergic contact dermatitis, also referred to as contact hypersensitivity, is mediated by CD8+ T cells, which are primed in lymphoid organs during the sensitization phase and are recruited in the skin upon re-exposure to the hapten. --- Explanation: This supports sensitization and T-cell priming as a discrete adaptive immune stage in allergic contact dermatitis.


MONDO:0005480

[PMID:19839974] [INDIRECT EVIDENCE] [SUPPORT] Allergic contact dermatitis, also referred to as contact hypersensitivity, is mediated by CD8+ T cells, which are primed in lymphoid organs during the sensitization phase and are recruited in the skin upon re-exposure to the hapten. --- Explanation: This supports effector T-cell recruitment to skin on hapten re-exposure as a separate mechanism node.


MONDO:0005480

[PMID:37700557] [INDIRECT EVIDENCE] [SUPPORT] BACKGROUND: Allergic contact dermatitis (ACD) is an inflammatory disease with a complex pathophysiology in which epidermal-resident memory CD8+ T (TRM ) cells play a key role. --- Explanation: This supports resident memory CD8-positive T cells as a distinct driver of allergic contact dermatitis flares.


MONDO:0005480

[PMID:37700557] [INDIRECT EVIDENCE] [SUPPORT] We show that loss of CD100 results in a reduced inflammatory response to DNFB with impaired production of IFNγ, IL-17A, CXCL1, CXCL2, CXCL5, and IL-1β and decreased recruitment of neutrophils to the epidermis. --- Explanation: This supports amplification of inflammatory cytokines, chemokines, and neutrophil recruitment as a discrete downstream mechanism in allergic contact dermatitis.

[DOI:10.1111/all.16642] [INDIRECT EVIDENCE] [SUPPORT] All allergens exhibited mixed effector immune responses, mainly type 1 and 3 immunity, and, to a lesser extent, type 2 immunity. --- Explanation: This human transcriptomic study supports mixed type 1 and type 3 cytokine programs, with lesser type 2 contributions, during allergic contact dermatitis elicitation.


MONDO:0005480

[PMID:39213029] [INDIRECT EVIDENCE] [SUPPORT] IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism. --- Explanation: This supports inflammatory fibroblast reprogramming as a distinct amplifying mechanism in allergic contact dermatitis.


MONDO:0005480

[PMID:34417985] [INDIRECT EVIDENCE] [SUPPORT] The complement system in sensory ganglion might play an essential role in forming pruritic and nociceptive sensations in ACD. --- Explanation: This supports complement-linked sensory pathway activation as a distinct neuroimmune mechanism in allergic contact dermatitis.


MAXO:0001014

[PMID:25102574] [SUPPORT] Accurate diagnosis, avoidance of identified allergens and protection from irritants are the key to successful treatment. --- Explanation: This supports avoidance of sensitizers and irritants as first-line disease management.

[PMID:9590995] [SUPPORT] Elimination of the offending agent and protection from further exposure are important in both diagnosis and management. --- Explanation: This independently supports exposure elimination and barrier protection as core treatment measures.


MAXO:0000058

[PMID:31757238] [SUPPORT] Topical corticosteroids can be used to treat exacerbations, but should be avoided in long-term treatment. --- Explanation: This supports topical corticosteroids for short-term treatment of inflammatory exacerbations.


MAXO:0000058

[PMID:16781290] [SUPPORT] CONCLUSIONS: Tacrolimus ointment 0.1% is well tolerated and significantly more effective than vehicle in treating chronically exposed, nickel-induced ACD. --- Explanation: This randomized clinical trial supports topical tacrolimus as an effective steroid-sparing option for chronic nickel-induced allergic contact dermatitis.

[PMID:14700441] [REFUTE] CONCLUSIONS: The application of topical pimecrolimus is ineffective in the treatment of ongoing Toxicodendron-induced ACD. --- Explanation: This placebo-controlled human study refutes efficacy of pimecrolimus for established Toxicodendron-induced allergic contact dermatitis.


MAXO:0000058

[DOI:10.3389/fmed.2023.1184289] [SUPPORT] The treatment goal is to avoid contact with the culprit agent and use topical and/or systemic corticosteroid therapy. --- Explanation: This review supports systemic corticosteroid therapy as a treatment option for allergic contact dermatitis alongside trigger avoidance.


hgnc:3748

[PMID:23343419] [SUPPORT] FLG mutation carriers with self-reported dermatitis have an increased risk of contact sensitization to substances other than nickel --- Explanation: This human population study supports FLG loss-of-function variants as a genetic risk factor for contact sensitization relevant to allergic contact dermatitis.


hgnc:3748

[PMID:23039796] [SUPPORT] Our results indicate that both FLG mutations and AD increase the risk of ICD. --- Explanation: This occupational case-control study supports FLG variants as an independent genetic susceptibility factor for irritant contact dermatitis.


ECTO:9001690

[PMID:25102574] [SUPPORT] Cumulative effects of water, soaps and detergents are the most common cause of ICD which affects the hands more often than any other site. --- Explanation: This supports wet work and detergent exposure as major environmental triggers of irritant contact dermatitis.


ECTO:9000063

[DOI:10.3389/fmed.2023.1184289] [SUPPORT] Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD. --- Explanation: This review identifies nickel as one of the most common sensitizing exposures in allergic contact dermatitis.


ECTO:9001808

[DOI:10.3389/fmed.2023.1184289] [SUPPORT] Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD. --- Explanation: This review identifies fragrance mix as a common sensitizer in patients patch tested for allergic contact dermatitis.


ECTO:7000130

[PMID:30465037] [SUPPORT] We report on a rare case of allergic contact dermatitis (ACD) from Mastisol liquid adhesive. --- Explanation: This case report supports Mastisol as a specific adhesive trigger of allergic contact dermatitis.


ECTO:7000130

[PMID:41784277] [SUPPORT] 2-octyl cyanoacrylate (2-OCA) topical skin adhesives are widely used for surgical wound closure but are increasingly associated with allergic contact dermatitis (ACD). --- Explanation: This systematic review supports 2-octyl cyanoacrylate as a specific surgical adhesive trigger of allergic contact dermatitis.

[PMID:41784277] [SUPPORT] Re-exposure markedly increased risk, with reaction rates rising from 1-3% after initial exposure to >20% in staged or repeat procedures in several cohorts. --- Explanation: This supports repeat exposure as an important risk amplifier for cyanoacrylate-triggered allergic contact dermatitis.


ECTO:0000726

[PMID:14700441] [SUPPORT] Plants of the Toxicodendron species cause allergic contact dermatitis (ACD) in 50% to 70% of the population. --- Explanation: This supports Toxicodendron plant exposure as a common and clinically important trigger of allergic contact dermatitis.

[PMID:27548435] [SUPPORT] Among various urushiol congeners, we identified diunsaturated pentadecylcatechol (C15:2) as the dominant antigen for CD1a-restricted T cells. --- Explanation: This supports urushiol III, the diunsaturated pentadecylcatechol congener, as a specific Toxicodendron allergen linked to poison ivy dermatitis.


MONDO:0015166


MONDO:0015166

[PMID:41152985] [INDIRECT EVIDENCE] [PARTIAL] core-binding factor acute myeloid leukemia patients, defined by the presence of a RUNX1::RUNX1T1 or CBFB::MYH11 fusion gene. --- Explanation: This abstract defines CBF-AML by RUNX1::RUNX1T1 or CBFB::MYH11 fusions, supporting the core-binding factor disruption described.


MAXO:0000647


MAXO:0000058


NCIT:C1806


MAXO:0000127


MAXO:0000747


HGNC.SYMBOL:RUNX1-RUNX1T1 Fusion

[PMID:22032582] [SUPPORT] The rearrangements t(8;21) and inv(16) involve the RUNX1/RUNX1T1 ( AML1-ETO ) and CBFB/MYH11 genes, respectively. --- Explanation: Abstract states RUNX1/RUNX1T1 is involved in the t(8;21) rearrangement defining CBF-AML.


HGNC.SYMBOL:CBFB-MYH11 Fusion

[PMID:22032582] [SUPPORT] The rearrangements t(8;21) and inv(16) involve the RUNX1/RUNX1T1 ( AML1-ETO ) and CBFB/MYH11 genes, respectively. --- Explanation: Abstract states CBFB/MYH11 is involved in the inv(16) rearrangement defining CBF-AML.


HGNC.SYMBOL:KIT


MONDO:0015166

[PMID:23590662] [SUPPORT] myeloblasts in the blood or bone marrow. --- Explanation: Abstract notes myeloblasts in the blood or bone marrow in AML.


MONDO:0009291

[PMID:27106217] [SUPPORT] GSDIII patients first presented before the age of 1.5 years, hepatomegaly was the most common presenting clinical sign. --- Explanation: Large international cohort confirms hepatomegaly as the most common presenting sign of GSD III, appearing before 1.5 years of age.


MONDO:0009291

[PMID:20301788] [SUPPORT] In infancy and early childhood, liver involvement presents as hepatomegaly and failure to thrive, with fasting ketotic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases. --- Explanation: GeneReviews describes fasting ketotic hypoglycemia as a key feature of GSD III in infancy and early childhood.

[PMID:38196773] [SUPPORT] Hypoglycemia was frequently reported in both adults and children, with more than half reporting hospitalizations due to hypoglycemia. --- Explanation: Patient burden study confirms high prevalence of hypoglycemia requiring hospitalization.


MONDO:0009291

[PMID:20301788] [SUPPORT] fasting ketotic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases. --- Explanation: GeneReviews lists hyperlipidemia as a key metabolic feature in GSD III.


MONDO:0009291

[PMID:34820282] [SUPPORT] In the GSD IIIa group, muscle weakness was a major feature, noted in 89% of the GSD IIIa cohort, a third of whom depended on a wheelchair or an assistive walking device. --- Explanation: Retrospective study of adults quantifies muscle weakness at 89% prevalence in GSD IIIa with significant functional impact.

[PMID:38196773] [SUPPORT] Adults most often reported muscle weakness as a top interfering symptom and the most important goal of a potential therapy. --- Explanation: Patient burden study identifies muscle weakness as the most impactful symptom from the patient perspective.


MONDO:0009291

[PMID:34820282] [SUPPORT] Asymptomatic left ventricular hypertrophy (LVH) was the most common cardiac manifestation, present in 43%. Symptomatic cardiomyopathy and reduced ejection fraction was evident in 10%. --- Explanation: Adult cohort study quantifies LVH at 43% and symptomatic cardiomyopathy at 10%.

[PMID:27106217] [SUPPORT] heart (cardiac involvement and cardiomyopathy, in 58 % and 15 %, respectively, generally presenting in early childhood) --- Explanation: International study reports cardiac involvement in 58% and cardiomyopathy in 15% of GSD III patients.


MONDO:0009291

[PMID:31263214] [SUPPORT] Creatine phosphokinase was also elevated with no significant correlation with age (p = 0.4). --- Explanation: Study shows CK is persistently elevated in GSD III patients regardless of age.


MONDO:0009291

[PMID:31263214] [SUPPORT] Liver fibrosis can occur at an early age, and may explain the decrease in aminotransferases and Glc4 with age. --- Explanation: Study demonstrates early onset of liver fibrosis in GSD III and its paradoxical relationship to normalizing aminotransferases.

[PMID:34820282] [SUPPORT] 28% developed decompensated liver disease and portal hypertension --- Explanation: Adult cohort shows significant progression to decompensated liver disease.


MONDO:0009291

[PMID:20301788] [SUPPORT] In infancy and early childhood, liver involvement presents as hepatomegaly and failure to thrive --- Explanation: GeneReviews identifies failure to thrive as a key early presentation.


MONDO:0009291

[PMID:31263214] [SUPPORT] Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter --- Explanation: Demonstrates elevated aminotransferases in early GSD III that paradoxically decrease with age.


MONDO:0009291

[PMID:11949933] [INDIRECT EVIDENCE] [SUPPORT] Most GSD-III patients have AGL deficiency in both the liver and muscle (type IIIa), but some have it in the liver but not muscle (type IIIb). --- Explanation: Confirms AGL deficiency causes GSD III with tissue-specific subtypes.

[PMID:27106217] [INDIRECT EVIDENCE] [SUPPORT] Glycogen storage disease type III (GSDIII) is a rare disorder of glycogenolysis due to AGL gene mutations, causing glycogen debranching enzyme deficiency and storage of limited dextrin. --- Explanation: Large international cohort study confirms AGL mutations cause debranching enzyme deficiency and limit dextrin accumulation.

[PMID:33368379] [INDIRECT EVIDENCE] [SUPPORT] Glycogen storage disorder type III (GSDIII) is a rare inborn error of metabolism due to loss of glycogen debranching enzyme activity, causing inability to fully mobilize glycogen stores and its consequent accumulation in various tissues, notably liver, cardiac and skeletal muscle. --- Explanation: Review confirms the pathophysiology of debranching enzyme loss causing glycogen accumulation in liver, cardiac, and skeletal muscle.


MONDO:0009291


MONDO:0009291

[PMID:31263214] [INDIRECT EVIDENCE] [SUPPORT] Liver fibrosis can occur at an early age, and may explain the decrease in aminotransferases and Glc4 with age. --- Explanation: Demonstrates that liver fibrosis occurs early in GSD III and that normalization of aminotransferases with age does not indicate hepatic improvement.

[PMID:27106217] [INDIRECT EVIDENCE] [SUPPORT] Chronic complications involved the liver (hepatic cirrhosis, adenoma(s), and/or hepatocellular carcinoma in 11 %) --- Explanation: Large cohort study documents hepatic cirrhosis and HCC as chronic complications of GSD III.

[PMID:34820282] [INDIRECT EVIDENCE] [SUPPORT] hepatomegaly and cirrhosis were the most common radiological findings; and 28% developed decompensated liver disease and portal hypertension, the latter being more prevalent in older patients. --- Explanation: Retrospective study of adults shows high rate of liver disease progression including cirrhosis and portal hypertension.


MONDO:0009291

[PMID:20301788] [INDIRECT EVIDENCE] [SUPPORT] Most individuals develop cardiac involvement with cardiac hypertrophy and/or cardiomyopathy. Skeletal myopathy manifesting as weakness may be evident in childhood and slowly progresses, typically becoming prominent in the third to fourth decade. --- Explanation: GeneReviews describes the progressive nature of cardiac and skeletal muscle involvement in GSD III.

[PMID:27106217] [INDIRECT EVIDENCE] [SUPPORT] heart (cardiac involvement and cardiomyopathy, in 58 % and 15 %, respectively, generally presenting in early childhood), and muscle (pain in 34 %). --- Explanation: Large international cohort quantifies cardiac involvement at 58% and cardiomyopathy at 15% in GSD III patients.

[PMID:34820282] [INDIRECT EVIDENCE] [SUPPORT] muscle weakness was a major feature, noted in 89% of the GSD IIIa cohort, a third of whom depended on a wheelchair or an assistive walking device. --- Explanation: Adult cohort study shows high prevalence and severity of muscle weakness in GSD IIIa, with significant functional disability.


MAXO:0000088

[PMID:20301788] [SUPPORT] Dietary management tailored to the individual patient remains the primary therapy. Frequent feeds (every 3-4 hours) are needed to maintain euglycemia in infancy. --- Explanation: GeneReviews establishes dietary management as the primary therapy with specific recommendations for meal frequency.

[PMID:2403059] [SUPPORT] Cornstarch therapy was associated with maintenance of normoglycemia, increased growth velocity, and decreased serum aminotransferase concentrations in all patients. --- Explanation: Clinical study demonstrates efficacy of cornstarch therapy in GSD III for glycemic control, growth, and liver function.

[PMID:25308556] [SUPPORT] A diet rich in fats as well as proteins and poor in carbohydrates could be a beneficial therapeutic choice for GSD III with cardiomyopathy. --- Explanation: Case report of two siblings shows high-fat low-carbohydrate diet improves cardiomyopathy in GSD IIIa.


MAXO:0010039

[PMID:20301788] [SUPPORT] Liver transplantation is reserved for those with severe hepatic cirrhosis, liver dysfunction, and/or hepatocellular carcinoma. Liver transplantation may exacerbate myopathy and cardiomyopathy. --- Explanation: GeneReviews describes liver transplantation indications and the important caveat that it may worsen muscle disease.


MAXO:0000079

[PMID:20301788] [SUPPORT] Once the AGL pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal and preimplantation genetic testing for a pregnancy at increased risk are possible. --- Explanation: GeneReviews outlines genetic counseling recommendations for GSD III families.


MONDO:0009291

[PMID:20301788] [SUPPORT] GSD III is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AGL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected with GSD III, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial AGL pathogenic variants. --- Explanation: GeneReviews confirms autosomal recessive inheritance of GSD III with standard Mendelian ratios for carrier parents.

[PMID:11949933] [SUPPORT] Deficiency of the glycogen debranching enzyme (gene, AGL) causes glycogen storage disease type III (GSD-III), an autosomal recessive disease affecting glycogen metabolism. --- Explanation: Confirms autosomal recessive inheritance and AGL gene involvement.


MONDO:1060134


MONDO:1060134

[PMID:38639096] [PARTIAL] By identifying and integrating the most gene-rich single-cell subclusters of atherosclerosis to date with a coronary artery disease framework of GRNs, GRN39 was identified and independently validated as being critical for the transformation of contractile SMCs into an osteogenic phenotype promoting advanced, symptomatic atherosclerosis. --- Explanation: Advanced symptomatic atherosclerosis, characterized by SMC transformation, leads to acute coronary events including myocardial infarction.


MONDO:1060134

[PMID:39518492] [INDIRECT EVIDENCE] [SUPPORT] We examine the cellular and molecular processes that drive the formation of calcified plaques, highlighting the roles of inflammation, lipid accumulation, and smooth muscle cell proliferation. --- Explanation: This review directly supports the role of lipid accumulation and inflammation in driving plaque formation in coronary artery disease.

[PMID:38639096] [INDIRECT EVIDENCE] [SUPPORT] Advanced stages of atherosclerosis progression and symptomatic carotid plaques were largely characterized by 3 smooth muscle cells (SMCs), and 3 macrophage subtype clusters with extracellular matrix organization/osteogenic (SMC), and M1-type proinflammatory/Trem2-high lipid-associated (macrophage) phenotypes. --- Explanation: Single-cell analysis confirms the presence of lipid-associated macrophages and smooth muscle cells in advanced atherosclerotic plaques, supporting foam cell formation and plaque progression.

[PMID:40594772] [INDIRECT EVIDENCE] [PARTIAL] Notable increases in VEGFA+ macrophages were discovered in the disturbed flow stimulation group, displaying a pronounced M1 pro-inflammatory phenotype associated with the severity of atherosclerosis and plaque stability. --- Explanation: This study identifies specific macrophage populations with pro-inflammatory phenotypes that contribute to atherosclerotic plaque formation and progression.


MONDO:1060134

[PMID:40594772] [INDIRECT EVIDENCE] [PARTIAL] CD36 + positive ECs exhibited significant senescence phenotypes following disturbed flow stimulation. --- Explanation: This study demonstrates that endothelial cells undergo senescence under disturbed flow conditions, a key mechanism in endothelial dysfunction during atherosclerosis.

[PMID:40594772] [INDIRECT EVIDENCE] [PARTIAL] Atherosclerosis tends to occur in regions of disturbed blood flow. This study explored how disturbed flow aggravates atherosclerosis using single-cell RNA-seq (scRNA-seq) datasets from mouse carotid arteries under disturbed flow and human carotid artery plaques. --- Explanation: Disturbed flow-induced endothelial dysfunction is a primary mechanism for atherosclerosis initiation in specific arterial regions.


MONDO:1060134

[PMID:40594772] [INDIRECT EVIDENCE] [PARTIAL] Notable increases in VEGFA+ macrophages were discovered in the disturbed flow stimulation group, displaying a pronounced M1 pro-inflammatory phenotype associated with the severity of atherosclerosis and plaque stability. --- Explanation: Pro-inflammatory macrophages contribute to plaque instability, which predisposes to rupture and thrombotic complications.

[PMID:38639096] [INDIRECT EVIDENCE] [PARTIAL] By identifying and integrating the most gene-rich single-cell subclusters of atherosclerosis to date with a coronary artery disease framework of GRNs, GRN39 was identified and independently validated as being critical for the transformation of contractile SMCs into an osteogenic phenotype promoting advanced, symptomatic atherosclerosis. --- Explanation: Smooth muscle cell transformation into osteogenic phenotypes contributes to plaque vulnerability and symptomatic disease, increasing risk of rupture and thrombotic events.


HGNC.SYMBOL:APOE

[PMID:40594772] [NO_EVIDENCE] GWAS-significant cardiovascular disease (CVD) risk genes were used to calculate risk gene scores for main cell populations. --- Explanation: GWAS studies have identified APOE as a significant cardiovascular disease risk gene contributing to coronary artery disease susceptibility.


HGNC.SYMBOL:LDLR

[PMID:40594772] [NO_EVIDENCE] GWAS-significant cardiovascular disease (CVD) risk genes were used to calculate risk gene scores for main cell populations. --- Explanation: LDLR is a well-established cardiovascular disease risk gene identified through genome-wide association studies.


HGNC.SYMBOL:PCSK9


HGNC.SYMBOL:9p21 Locus


MONDO:0009026

[PMID:20301680] [SUPPORT] Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; --- Explanation: GeneReviews identifies failure to thrive from severe feeding difficulty as a typical early clinical feature of HRAS-related Costello syndrome.

[PMID:34508588] [SUPPORT] In CS, poor weight gain and growth are not caused by low caloric intake. Here, we show that constitutive plasma membrane translocation and activation of the GLUT4 glucose transporter, via reactive oxygen species-dependent AMP-activated protein kinase α and p38 hyperactivation, occurs in primary fibroblasts of CS patients, resulting in accelerated glycolysis and increased fatty acid synthesis and storage as lipid droplets. --- Explanation: Patient fibroblast study expands the mechanistic basis of growth failure by showing increased energetic expenditure and dysregulated metabolism in Costello syndrome.


MONDO:0009026

[PMID:20301680] [SUPPORT] Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); --- Explanation: Updated GeneReviews description supports coarse facial features as a characteristic and typically present dysmorphic feature of Costello syndrome.


MONDO:0009026

[PMID:12210337] [SUPPORT] Cardiac hypertrophy was reported in 34%, which involved the left ventricle in 50% and was usually consistent with classic hypertrophic cardiomyopathy (HCM). --- Explanation: Pooled clinical cohort data confirm hypertrophic cardiomyopathy as a frequent cardiac manifestation of Costello syndrome.


MONDO:0009026

[PMID:38415356] [SUPPORT] During early childhood, 50% of patients develop multifocal atrial tachycardia, a treatment-resistant tachyarrhythmia of unknown pathogenesis. --- Explanation: Establishes 50% prevalence of MAT in Costello syndrome patients, occurring in early childhood as a treatment-resistant arrhythmia.

[PMID:20301680] [SUPPORT] and arrhythmia (usually supraventricular tachycardia, especially abnormal atrial rhythm / multifocal atrial tachycardia or ectopic atrial tachycardia). --- Explanation: GeneReviews supports multifocal atrial tachycardia as the characteristic Costello syndrome arrhythmia phenotype.


MONDO:0009026

[PMID:20301680] [SUPPORT] Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; --- Explanation: GeneReviews identifies short stature as a typical component of the core Costello syndrome phenotype.


MONDO:0009026

[PMID:22495831] [SUPPORT] An evaluation of 15 adult patients 18-32 years of age revealed that 12 had moderate to severe intellectual disability and most live at home without constant medical care. --- Explanation: Nationwide survey data support intellectual disability as a frequent long-term neurodevelopmental manifestation of Costello syndrome.


MONDO:0009026

[PMID:20301680] [SUPPORT] diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; --- Explanation: GeneReviews identifies diffuse joint laxity as part of the characteristic musculoskeletal phenotype of Costello syndrome.


MONDO:0009026

[PMID:20301680] [SUPPORT] diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; --- Explanation: GeneReviews supports ulnar deviation of the wrists and fingers as a characteristic orthopedic feature of Costello syndrome.


MONDO:0009026

[PMID:20301680] [SUPPORT] papillomata of the face and perianal region; --- Explanation: GeneReviews supports papillomata as a typical ectodermal manifestation, especially affecting the face and perianal region.


MONDO:0009026

[PMID:16443854] [SUPPORT] Individuals with CS have an increased risk of malignancy, suggested to be about 17%. --- Explanation: Establishes the approximately 17% lifetime malignancy risk in Costello syndrome.

[PMID:20301680] [SUPPORT] Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults. --- Explanation: Updated GeneReviews summary independently supports occasional but clinically important malignancy risk in Costello syndrome.


MONDO:0009026

[PMID:35230976] [INDIRECT EVIDENCE] [SUPPORT] Germline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies. --- Explanation: This mixed-model study supports pathway activation as the shared upstream pathogenic framework for Costello syndrome.


MONDO:0009026


MONDO:0009026

[PMID:35230976] [INDIRECT EVIDENCE] [SUPPORT] The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of CS mice that were also found in the cell models of the disease. The underpinning mechanisms involved the inhibition of the AMPK signaling pathway by mutant forms of HRAS, leading to alteration of mitochondrial proteostasis and bioenergetics. --- Explanation: This Asta-linked study directly supports a discrete cardiac and muscular bioenergetic mechanism downstream of mutant HRAS.


MONDO:0009026

[PMID:38415356] [INDIRECT EVIDENCE] [SUPPORT] Mutant ACMs demonstrated elevated gene expression (ie, ISL1, TBX3, TBX18) related to intracellular calcium homeostasis, heart rate, RAS signaling, and induction of pacemaker-nodal-like transcriptional programming. --- Explanation: This human iPSC-derived atrial cardiomyocyte model directly supports a discrete transcriptional reprogramming step in Costello syndrome arrhythmogenesis.


MONDO:0009026

[PMID:38415356] [INDIRECT EVIDENCE] [SUPPORT] Electrophysiological assessment revealed an increased number of pacemaker-like cells with elevated funny current densities among mutant ACMs. --- Explanation: The iPSC atrial cardiomyocyte study identifies the electrophysiologic substrate immediately upstream of MAT.


MONDO:0009026

[PMID:34508588] [INDIRECT EVIDENCE] [SUPPORT] In CS, poor weight gain and growth are not caused by low caloric intake. Here, we show that constitutive plasma membrane translocation and activation of the GLUT4 glucose transporter, via reactive oxygen species-dependent AMP-activated protein kinase α and p38 hyperactivation, occurs in primary fibroblasts of CS patients, resulting in accelerated glycolysis and increased fatty acid synthesis and storage as lipid droplets. An accelerated autophagic flux was also identified as contributing to the increased energetic expenditure in CS. --- Explanation: This patient fibroblast study directly supports a distinct metabolic disease mechanism explaining the disproportionate growth failure of Costello syndrome.


MONDO:0009026

[PMID:10712202] [INDIRECT EVIDENCE] [SUPPORT] We found that impaired production of elastic fibers by these fibroblasts is associated with a functional deficiency of the 67-kD elastin-binding protein (EBP), which is normally required to chaperone tropoelastin through the secretory pathways and to its extracellular assembly. --- Explanation: This patient skin fibroblast study supports a specific extracellular matrix defect that plausibly underlies connective tissue manifestations in Costello syndrome.


MONDO:0009026

[PMID:31250618] [INDIRECT EVIDENCE] [SUPPORT] Induced pluripotent stem cells (iPSCs) derived from Costello syndrome showed increased production of cortical neurons associated with extended progenitor phase (Rooney et al., 2016). --- Explanation: This review cites disease-relevant iPSC evidence that Costello syndrome disrupts early cortical developmental programs.

[PMID:31250618] [INDIRECT EVIDENCE] [SUPPORT] During transition from neurogenesis to gliogenesis, Paquin et al. (2009) showed that variants found in Costello syndrome suppress neurogenesis but promote astrogenesis. --- Explanation: This supports a second discrete developmental mechanism involving an abnormal neurogenesis-gliogenesis switch in Costello syndrome.


MONDO:0009026

[PMID:20301680] [INDIRECT EVIDENCE] [SUPPORT] Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults. --- Explanation: GeneReviews supports a dedicated neoplasia-predisposition branch within the Costello syndrome causal graph.


MAXO:0000003

[PMID:20301680] [SUPPORT] echocardiography with electrocardiogram at the time of diagnosis with subsequent follow up by a cardiologist; --- Explanation: GeneReviews recommends serial cardiac surveillance with echocardiography and electrocardiography in HRAS-related Costello syndrome.


MAXO:0000126

[PMID:20301680] [SUPPORT] abdominal and pelvic ultrasound examinations to screen for rhabdomyosarcoma and neuroblastoma every three to six months until age eight to ten years may be considered; annual urinalysis for evidence of hematuria to screen for bladder cancer beginning at age ten years. --- Explanation: Updated GeneReviews surveillance guidance supports tumor screening in childhood and bladder cancer surveillance later in life.


MAXO:0000058

[PMID:20301680] [SUPPORT] Targeted therapy: Trametinib (MEK inhibitor) for treatment of hypertrophic cardiomyopathy with heart failure that is refractory to standard treatment. --- Explanation: Updated GeneReviews documents trametinib as a targeted option for severe Costello syndrome cardiomyopathy refractory to standard management.


hgnc:5173

[PMID:16443854] [SUPPORT] These results confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS. --- Explanation: Large genotype-phenotype study of 43 Costello syndrome cases confirming HRAS as the causative gene.


MONDO:0009026

[PMID:20301680] [SUPPORT] GENETIC COUNSELING: Costello syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. --- Explanation: GeneReviews directly supports autosomal dominant inheritance with predominant de novo occurrence in Costello syndrome.

[PMID:16443854] [SUPPORT] Analysis of parental DNA samples was possible in 16 cases for both parents and in three cases for one parent, and confirmed the mutations as de novo in all of these cases. --- Explanation: This cohort study provides direct human evidence that Costello syndrome HRAS mutations are usually de novo.

[PMID:21438134] [SUPPORT] De novo origin of the missense mutation was documented in eight families, and occurred in the paternal germline in all five informative trios. --- Explanation: This Costello syndrome cohort provides direct evidence for paternal germline bias among informative de novo HRAS cases.


MONDO:0001491

[PMID:34164212] [SUPPORT] Cough variant asthma (CVA) is a phenotype of asthma which lacks wheezing or dyspnea, and consistently one of the most common causes of chronic cough worldwide. --- Explanation: Establishes chronic cough as the defining and predominant symptom of CVA.

[PMID:35127763] [SUPPORT] CVA reported more severe cough on Visual Analog Scale, Cough Evaluation Test, and Leicester Cough Questionnaire --- Explanation: Demonstrates that cough severity is paradoxically higher in CVA than classic asthma despite lower inflammatory biomarkers.


MONDO:0001491

[PMID:34164212] [SUPPORT] CVA and non-asthmatic eosinophilic bronchitis (NAEB) shares common feature such as chronic dry cough, eosinophilic inflammation, and development of chronic airflow obstruction (CAO) and asthma in a subset of patients. --- Explanation: Confirms chronic dry cough as a shared feature of CVA.


MONDO:0001491

[PMID:34164212] [SUPPORT] Cough variant asthma (CVA) is a phenotype of asthma which lacks wheezing or dyspnea --- Explanation: Confirms that CVA characteristically lacks wheezing, making it an occasional rather than defining feature.


MONDO:0001491

[PMID:35127763] [INDIRECT EVIDENCE] [SUPPORT] Cough variant asthma is distinctive from classic asthma in regard to clinical features, lung function, and airway inflammation. --- Explanation: Large multicenter APAC cohort demonstrates that CVA has measurable but lower type 2 inflammatory markers compared to classic asthma.

[PMID:35127763] [INDIRECT EVIDENCE] [SUPPORT] No correlation was found between cough assessment outcomes and sputum eosinophil count, blood eosinophil count, FENO, spirometry variables, or PD20-FEV1. --- Explanation: Demonstrates that cough severity in CVA is dissociated from eosinophilic inflammation intensity, suggesting additional cough-driving mechanisms beyond eosinophilia.

[PMID:38566832] [INDIRECT EVIDENCE] [SUPPORT] In the three groups of CVA patients, after receiving budesonide inhalation combined with conventional symptomatic treatment, the expression levels of serum IL-5, IL-6, IL-8, TNF-α, TGF-β1, and IgE and number of eosinophils significantly decreased (P <0.05). --- Explanation: Confirms the presence of eosinophilic and cytokine-mediated inflammation in CVA that responds to inhaled corticosteroid treatment.

[PMID:34164212] [INDIRECT EVIDENCE] [SUPPORT] approximately 30% to 50% of people with chronic cough have eosinophilic airway inflammation, the presence of which can be confirmed by sputum eosinophilia or elevated exhaled nitric-oxide levels. --- Explanation: Establishes eosinophilic airway inflammation as a common feature of chronic cough conditions including CVA.


MONDO:0001491


MONDO:0001491

[PMID:35127763] [INDIRECT EVIDENCE] [SUPPORT] CVA subjects showed a higher proportion of female (67.1 vs. 55.3%, P = 0.0084), abnormal laryngopharyngeal sensations (71 vs. 51%, p < 0.0001) than CA, but presented with near normal spirometry and higher methacholine PD20-FEV1 values --- Explanation: Demonstrates AHR in CVA (positive methacholine challenge) but at milder levels than classic asthma, with higher PD20-FEV1 values.

[PMID:34164212] [INDIRECT EVIDENCE] [SUPPORT] The distinctive characteristic of these conditions is the presence of airway hyperresponsiveness in CVA but not in NAEB. --- Explanation: Establishes AHR as the key distinguishing feature between CVA and non-asthmatic eosinophilic bronchitis.


MONDO:0001491

[PMID:39534772] [INDIRECT EVIDENCE] [SUPPORT] The symptoms of cough hypersensitivity may not distinguish between asthmatic cough and RCC. This suggests that chronic cough is the primary diagnosis in both phenotypes. It indicates a shared mechanism in their cough pathogenesis, despite having potentially different treatable traits. --- Explanation: Demonstrates that cough hypersensitivity is a shared mechanism between CVA and refractory chronic cough, supporting cough reflex hypersensitivity as a core feature of CVA.

[PMID:37969279] [INDIRECT EVIDENCE] [SUPPORT] Cough reflex hypersensitivity (CRH) has also been reported in asthma, COPD, bronchiectasis, ILD and sarcoidosis. --- Explanation: State-of-the-art review confirms cough reflex hypersensitivity in asthma, supporting it as a mechanism in CVA.

[PMID:35127763] [INDIRECT EVIDENCE] [SUPPORT] abnormal laryngopharyngeal sensations (71 vs. 51%, p < 0.0001) than CA --- Explanation: Higher prevalence of abnormal laryngopharyngeal sensations in CVA compared to classic asthma supports heightened cough reflex sensitivity as a prominent feature.


MONDO:0001491

[PMID:35095550] [INDIRECT EVIDENCE] [SUPPORT] SAD occurred in 73 (60.8%) patients with CVA before treatment. --- Explanation: Demonstrates high prevalence of small airway dysfunction in corticosteroid-naive CVA patients.

[PMID:35095550] [INDIRECT EVIDENCE] [SUPPORT] Among 105 patients who completed 2 months of antiasthmatic treatment and repeatedly experienced spirometry measurement, 57 (54.3%) patients still had SAD, despite a significant improvement in cough VAS, sputum eosinophils, FeNO, FEF50% pred, and PEF% pred (all p < 0.01). --- Explanation: SAD persists in over half of CVA patients after 2 months of treatment despite improvement in other parameters, suggesting a treatment-resistant component.

[PMID:35095550] [INDIRECT EVIDENCE] [SUPPORT] Small airway dysfunction occurred in over half of patients with CVA and persisted after short-term antiasthmatic treatment, which showed distinctive clinical and pathophysiological features. --- Explanation: Confirms SAD as a distinct pathophysiological feature of CVA.


MAXO:0000314

[PMID:38566832] [SUPPORT] Budesonide inhalation combined with conventional symptomatic treatment can significantly reduce the levels of serum inflammatory factors in patients with CVA to reduce inflammation and the allergic response, thereby reducing the cough symptom score, improving pulmonary function, and improving therapeutic efficacy. --- Explanation: Demonstrates efficacy of inhaled budesonide in reducing inflammation and improving symptoms in CVA, with biomarker-guided early response prediction.

[PMID:34164212] [SUPPORT] Inhaled corticosteroids (ICSs) are the first-line treatment, and leukotriene receptor antagonists are also effective, in patients with both CVA and NAEB. --- Explanation: Confirms ICS as first-line treatment for CVA.


MAXO:0000316

[PMID:34164212] [SUPPORT] Coughing is responsive to bronchodilators such as beta-agonists in CVA, but such feature has not been clarified in NAEB. --- Explanation: Confirms bronchodilator responsiveness of cough as a diagnostic feature of CVA.


MAXO:0000315

[PMID:34164212] [SUPPORT] Inhaled corticosteroids (ICSs) are the first-line treatment, and leukotriene receptor antagonists are also effective, in patients with both CVA and NAEB. --- Explanation: Confirms leukotriene receptor antagonists as an effective treatment for CVA.


MONDO:0016063

[PMID:17526800] [SUPPORT] Cowden Syndrome (CS), an adult-onset condition recognised by mucocutaneous signs, with a risk of cancers, in particular those of the thyroid and breast. --- Explanation: Establishes mucocutaneous signs as the defining clinical feature of Cowden syndrome in PTEN mutation carriers.


MONDO:0016063

[PMID:17526800] [SUPPORT] Bannayan-Riley-Ruvalcaba syndrome (BRRS), with childhood onset, macrocephaly, lipomas and developmental delay, and Cowden Syndrome (CS), an adult-onset condition recognised by mucocutaneous signs, with a risk of cancers, in particular those of the thyroid and breast. --- Explanation: Documents macrocephaly as a characteristic feature across the PTEN mutation phenotypic spectrum, particularly in the childhood-onset BRRS form.


MONDO:0016063

[PMID:23335809] [SUPPORT] Elevated SIRs were found mainly for female breast cancer (39.1, 95% CI 24.8 to 58.6), thyroid cancer in women (43.2, 95% CI 19.7 to 82.1) and in men (199.5, 95% CI 106.39 to 342.03), melanoma in women (28.3, 95% CI 7.6 to 35.4) and in men (39.4, 95% CI 10.6 to 100.9), and endometrial cancer (48.7, 95% CI 9.8 to 142.3). --- Explanation: Demonstrates markedly elevated standardized incidence ratios (SIR 39.1) for breast cancer in female PTEN mutation carriers, confirming the substantially increased breast cancer risk in Cowden syndrome.


MONDO:0016063

[PMID:32533092] [SUPPORT] There is strong evidence of an increased risk of thyroid carcinoma in PHTS with evidence that this can arise at relatively young ages. --- Explanation: Confirms strong clinical evidence for increased thyroid carcinoma risk in PTEN hamartoma tumor syndrome/Cowden syndrome.


MONDO:0016063

[PMID:23335809] [SUPPORT] Elevated SIRs were found mainly for female breast cancer (39.1, 95% CI 24.8 to 58.6), thyroid cancer in women (43.2, 95% CI 19.7 to 82.1) and in men (199.5, 95% CI 106.39 to 342.03), melanoma in women (28.3, 95% CI 7.6 to 35.4) and in men (39.4, 95% CI 10.6 to 100.9), and endometrial cancer (48.7, 95% CI 9.8 to 142.3). --- Explanation: Documents a substantially elevated standardized incidence ratio (SIR 48.7) for endometrial cancer in PHTS, confirming uterine cancer as a major cancer risk in Cowden syndrome.


MONDO:0016063

[PMID:37810307] [SUPPORT] Lhermitte-Duclos disease (LDD) is a rare tumor, with only about 300 reported cases. It often shows comorbidity with Cowden syndrome (CS); however, it can occur by itself. --- Explanation: Confirms the well-established association between Lhermitte-Duclos disease and Cowden syndrome in a systematic review of 302 cases, with 32.8% of LDD showing CS comorbidity.


MONDO:0016063

[PMID:32533092] [SUPPORT] Polyps are common in PHTS, and these are typically hamartomas, although other types can also occur. --- Explanation: Confirms hamartomatous GI polyps as a common feature of PTEN hamartoma tumor syndrome/Cowden syndrome.


MONDO:0016063

[PMID:18781191] [INDIRECT EVIDENCE] [SUPPORT] PTEN is located on chromosome 10q22-23 and negatively regulates the prosurvival PI3K/Akt/mTOR pathway through its lipid phosphatase activity. Loss of PTEN activates this pathway and leads to increased cellular growth, migration, proliferation, and survival. --- Explanation: Directly establishes that PTEN loss leads to PI3K/AKT/mTOR hyperactivation driving cellular overgrowth, the central molecular mechanism of Cowden syndrome.

[PMID:30614812] [INDIRECT EVIDENCE] [SUPPORT] The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. --- Explanation: Confirms PTEN's role as a counterbalance to PI3K/AKT/mTOR and links germline PTEN mutations to the full PHTS spectrum including Cowden syndrome.


MONDO:0016063


MONDO:0016063

[PMID:18781191] [INDIRECT EVIDENCE] [SUPPORT] The PTEN hamartoma tumor syndromes (PHTS) are a collection of rare clinical syndromes characterized by germline mutations of the tumor suppressor PTEN. These syndromes are driven by cellular overgrowth, leading to benign hamartomas in virtually any organ. --- Explanation: Confirms that PTEN loss drives cellular overgrowth leading to hamartomas across organ systems, which is the hallmark of Cowden syndrome pathology.


MONDO:0016063

[PMID:23335809] [INDIRECT EVIDENCE] [SUPPORT] Cumulative cancer risks at age 70 were 85% (95% CI 70% to 95%) for any cancer, 77% (95% CI 59% to 91%) for female breast cancer, and 38% (95% CI 25% to 56%) for thyroid cancer. --- Explanation: Quantifies the markedly elevated cumulative cancer risks in PTEN mutation carriers, establishing the clinical significance of increased cancer risk in PHTS/Cowden syndrome.

[PMID:32533092] [INDIRECT EVIDENCE] [SUPPORT] The projected estimated lifetime risks of cancer in individuals with PHTS range from 85 to 89% for any cancer, 67 to 85% for female breast cancer, 6 to 38% for thyroid cancer, 2 to 28% for endometrial cancer, 2 to 34% for renal cancer, 9 to 20% for colorectal cancer and 0 to 6% for melanoma. --- Explanation: Provides European expert consensus estimates for organ-specific lifetime cancer risks in PHTS/Cowden syndrome, supporting the multi-organ cancer predisposition mechanism.


MAXO:0000126

[PMID:32533092] [SUPPORT] Recommendations were put forward for surveillance for breast, thyroid and renal cancers. Limited recommendations were developed for other sites including endometrial, colon and skin. --- Explanation: Provides evidence-based surveillance recommendations for PHTS/Cowden syndrome from the European Reference Network for Genetic Tumour Risk Syndromes.


MAXO:0000004

[PMID:32533092] [SUPPORT] Risk reduction surgery should be offered using the same considerations as for women with germline BRCA1/BRCA2 pathogenic variants --- Explanation: Supports offering prophylactic mastectomy in PTEN mutation carriers following the same approach as for BRCA1/BRCA2, given comparable breast cancer risk levels.


MAXO:0000058

[PMID:18781191] [SUPPORT] Concomitant with improved understanding of the biology of PTEN and the PI3K/Akt/mTOR pathway, inhibitors of this pathway are being developed as anticancer agents. These medications could have applications for patients with PHTS, for whom no medical options currently exist. --- Explanation: Establishes the rationale for mTOR/PI3K inhibitor therapy in PTEN hamartoma tumor syndrome based on the underlying molecular mechanism. Note: this is speculative expert opinion from a 2008 review, not clinical trial data.


MAXO:0000079

[PMID:31433956] [SUPPORT] Timely diagnosis and understanding the natural history of PHTS are vital because early recognition enables gene-informed management, particularly as related to high-risk cancer surveillance and addressing the neurodevelopmental symptoms. --- Explanation: Highlights the importance of genetic diagnosis enabling gene-informed counseling and management in PHTS/Cowden syndrome.


hgnc:9588

[PMID:21194675] [SUPPORT] Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome are allelic, defined by germline PTEN mutations, and collectively referred to as PTEN hamartoma tumor syndrome. --- Explanation: Establishes PTEN germline mutations as the defining genetic cause of Cowden syndrome in a large prospective cohort of 3042 probands.


hgnc:37212

[PMID:21177507] [SUPPORT] Germline KILLIN methylation is common among patients with Cowden syndrome or Cowden-like syndrome and is associated with increased risks of breast and renal cancer over PTEN mutation-positive individuals. --- Explanation: Establishes KLLN germline methylation as a distinct molecular subtype of Cowden syndrome with measurably elevated cancer risks.


hgnc:8975

[PMID:23246288] [SUPPORT] We report that 8 of 91 (8.8%) unrelated CS individuals without germline PTEN mutations carried 10 germline PIK3CA mutations (7 missense, 1 nonsense, and 2 indels) and 2 (2.2%) AKT1 mutations. These mutations result in significantly increased P-Thr308-AKT and increased cellular PIP3. --- Explanation: Directly identifies PIK3CA germline mutations in Cowden syndrome patients lacking PTEN mutations, confirming PIK3CA as a causative gene in Cowden syndrome 3.


hgnc:10681

[PMID:18678321] [SUPPORT] Germline SDH mutations/variants occur in a subset of PTEN mutation-negative CS/CS-like individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. --- Explanation: Establishes SDHB germline mutations as a causative factor in Cowden syndrome 4, found in PTEN-mutation-negative individuals with elevated cancer risk.


MONDO:0005011

[PMID:29246562] [SUPPORT] The most frequent symptoms are abdominal pain and diarrhoea, which can seriously affect patients' quality of life.

[PMID:33946069] [SUPPORT] In Crohn's disease, inflammation causes pain.

[PMID:35380673] [SUPPORT] The prevalence of pain was high in IBD patients ... and higher in CD patients.

[PMID:33836648] [NO_EVIDENCE] Using the patients'' self-reported information, we identified two subpopulations of Crohn's disease; these subpopulations differ in disease severity, associations with smoking, and genetic transmission patterns. --- Explanation: While this reference focuses on identifying subpopulations with varying disease severity, it underscores the heterogeneity of Crohn’s disease symptoms, indirectly supporting that abdominal pain is a frequent symptom.


MONDO:0005011

[PMID:22230271] [PARTIAL] Patients may experience diarrhea, abdominal pain, fever, weight loss, abdominal masses, and anemia. --- Explanation: This reference supports the presence of diarrhea and weight loss as frequent symptoms of Crohn's disease. However, it does not explicitly discuss malnutrition as a common sequela or confirm that these phenotypes are highly frequent.

[PMID:38036713] [PARTIAL] Malnutrition might play a key role in the prognosis of patients with Crohn's disease (CD) ... Forty-one patients (24.8%) had body weight loss whereas 124 patients (75.2%) had no body weight loss. --- Explanation: This reference mentions weight loss and suggests a role for malnutrition in Crohn's disease prognosis, but does not confirm high frequency of gastrointestinal symptoms like diarrhea.


MONDO:0005011

[PMID:23111414] [SUPPORT] A high percentage of CD patients suffer from fatigue. --- Explanation: This reference confirms that fatigue is a common symptom among Crohn's disease patients.

[PMID:37569413] [SUPPORT] Despite high prevalence and importance, the symptom is often underestimated in clinical practice. --- Explanation: The reference articulates the high prevalence of fatigue in inflammatory diseases, supporting the statement that fatigue is common among Crohn's disease patients.


MONDO:0005011

[PMID:29043578] [SUPPORT] The most common phenotype is stricturing disease which can lead to obstructive-like symptoms. --- Explanation: The reference states that stricturing disease, a common phenotype of Crohn's disease, can lead to obstructive-like symptoms, supporting the statement that intestinal obstruction due to stricturing disease occurs occasionally in Crohn's disease.

[PMID:34014617] [SUPPORT] Approximately 70% of patients inevitably develop fibrosis-associated intestinal stricture after 10 years of CD diagnosis, which seriously affects their quality of life. --- Explanation: The reference indicates that a significant proportion of Crohn's disease patients develop intestinal strictures, which can lead to obstruction, supporting the statement.

[PMID:37973225] [SUPPORT] Benign etiologies of colonic obstructions include...inflammatory processes such as Crohn's disease. --- Explanation: The reference confirms that inflammatory processes like Crohn's disease can lead to colonic obstructions, supporting the statement.


MONDO:0005011

[PMID:21122514] [SUPPORT] The most common extraintestinal manifestation, articular involvement, occurs in 16% to 33% of inflammatory bowel disease patients. These arthropathies may increase morbidity, resulting in a worse quality of life compared with inflammatory bowel disease patients without arthropathies. --- Explanation: The literature indicates that arthritis is a common extraintestinal manifestation of Crohn's disease, affecting both large and small joints.

[PMID:36730654] [SUPPORT] The prevalence of peripheral arthritis was significantly higher in CD-FMF group (37.5% vs. 10.4%, respectively, P =0.04). --- Explanation: This study supports the occurrence of arthritis in Crohn's disease patients, particularly noting a higher prevalence in patients with coexisting FMF.


MONDO:0005011

[PMID:16143688] [SUPPORT] Erythema nodosum is a common cause of tender red nodules of the shins. Management includes leg elevation, NSAIDs, and potassium iodide. --- Explanation: The reference confirms that erythema nodosum, characterized by tender red nodules on the shins, is associated with inflammatory bowel disease, which includes Crohn's disease.

[PMID:24746312] [SUPPORT] Erythema nodosum (EN) is clinically the most frequent form of panniculitis and is considered a reactive process that may be triggered by a wide variety of stimuli. Whilst up to 55% of EN is considered idiopathic, the most common causes include infections, drugs, systemic illnesses such as sarcoidosis and inflammatory bowel disease, pregnancy, and malignancy. --- Explanation: The reference supports the statement by mentioning that erythema nodosum is commonly triggered by systemic illnesses, including inflammatory bowel disease, which encompasses Crohn's disease.


MONDO:0005011

[PMID:2052301] [PARTIAL] Seven patients had uveitis, eight had episcleritis, and four had anterior scleritis. --- Explanation: The literature confirms that uveitis is a type of ocular inflammation associated with Crohn's disease, but it does not specify the frequency as 'occasional'.

[PMID:29102673] [PARTIAL] This case of Crohn's disease and uveitis is unusual in that ocular inflammation preceded intestinal involvement, with the atypical feature of chronic intermediate uveitis. --- Explanation: The literature provides a case of uveitis associated with Crohn's disease but does not specify the frequency as 'occasional'.


MONDO:0005011

[PMID:20456309] [SUPPORT] Fatigue is common, disabling yet underappreciated, in patients with chronic diseases, including inflammatory bowel disease (IBD). --- Explanation: The literature explicitly states that fatigue is common in IBD, which includes Crohn's Disease.

[PMID:17560419] [PARTIAL] Pain and depression are associated with inflammatory bowel disease, and their control benefits patients. --- Explanation: This reference mentions pain and depression as associated with IBD but does not specifically mention fatigue. However, the association with other systemic symptoms suggests a partial support.


MONDO:0005011

[PMID:30244270] [SUPPORT] Crohn's disease is a chronic inflammatory bowel disease. The disease is characterized by acute exacerbations with diarrhea, abdominal pain, fever, anorexia, intestinal bleeding, and weight loss. --- Explanation: This reference confirms that fever is a symptom associated with acute exacerbations of Crohn's disease.

[PMID:921308] [SUPPORT] In 32 patients with Crohn's disease which started in childhood, abdominal pain, diarrhoea, and weight loss were the common presenting symptoms, but unexplained fever and failure to grow were also prominent. --- Explanation: This reference supports the statement by indicating that fever is a prominent symptom in patients with Crohn's disease.

[PMID:27743896] [SUPPORT] A frequent problem in CD is the discrimination of fever caused by exacerbated bowel inflammation or IAA. --- Explanation: This reference supports the statement by highlighting that fever is a frequent issue in Crohn's disease, especially during exacerbations.

[PMID:31347993] [SUPPORT] A 23-year-old man with a known history of Crohn's disease (CD), who underwent an ileocaecal resection for localized disease activity three months ago, suffered from persistent fever with chills since 10 days. --- Explanation: This reference supports the statement by providing a case where a patient with Crohn's disease experienced persistent fever.


MONDO:0005011


MONDO:0005011

[PMID:18849966] [INDIRECT EVIDENCE] [SUPPORT] ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway --- Explanation: This study demonstrates that autophagy proteins ATG16L1 and ATG5 are essential for Paneth cell function and that defects cause granule abnormalities linked to Crohn's disease.


MONDO:0005011

[PMID:34313550] [INDIRECT EVIDENCE] [SUPPORT] Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects. --- Explanation: Supports epithelial barrier dysfunction as a mechanistic bridge between dysbiosis and pathological immune activation in Crohn disease.


MONDO:0005011

[PMID:34313550] [INDIRECT EVIDENCE] [SUPPORT] Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects. --- Explanation: Supports active intestinal inflammation as a proximal tissue-level step linking barrier and immune dysregulation to Crohn manifestations.

[PMID:36720220] [INDIRECT EVIDENCE] [SUPPORT] Our integrated datasets revealed organ- and compartment-specific responses to acute and chronic inflammation; most immune changes were in cell composition, whereas transcriptional changes dominated among epithelial and stromal cells. --- Explanation: Supports epithelial and stromal injury as a defining feature of active Crohn inflammation in affected intestinal tissue.


MAXO:0000058

[PMID:12786608] [SUPPORT] The mainstay of current medical treatment for mild to moderately active stages of Crohn's disease includes aminosalicylates, antibiotics, glucococorticosteroids and immunomodulators. --- Explanation: This reference states that aminosalicylates are included in the main treatments for mild to moderately active Crohn's disease.

[PMID:34797442] [SUPPORT] 5-aminosalicylates (5-ASA) are frequently used in the management of Crohn's disease. --- Explanation: This reference supports the use of aminosalicylates for Crohn's disease treatment.

[PMID:17339853] [REFUTE] Sulfasalazine and mesalazine are useful for the treatment of both active and quiescent ulcerative colitis, whereas they have no clinical effect on either active or inactive Crohn's disease. --- Explanation: This reference explicitly states that aminosalicylates have no clinical effect on Crohn's disease.


MAXO:0000058

[PMID:24532122] [SUPPORT] Corticosteroids have been used for decades to treat active Crohn's disease and remain the mainstay in the management of moderate-to-severe relapses in Crohn's disease. --- Explanation: This indicates that corticosteroids are indeed a primary treatment option for managing flare-ups in Crohn's disease.

[PMID:32653651] [SUPPORT] corticosteroids are crucial for the induction of remission of moderate‑to‑severe flares in both UC and Crohn's disease. --- Explanation: This strengthens the claim that corticosteroids are used for short-term control during flare-ups to reduce inflammation in Crohn's disease.

[PMID:18239408] [SUPPORT] The management of Crohn's disease usually consists of a succession of short-term acute phase treatments followed by a long-term maintenance therapy. --- Explanation: This reinforces that corticosteroids are part of the short-term treatment strategy to control flare-ups in Crohn's disease.


MAXO:0000058

[PMID:17105689] [SUPPORT] The immunomodulatory drugs in the IBD arsenal include azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, and tacrolimus. --- Explanation: The provided literature supports the statement that drugs like azathioprine and methotrexate are used as immunomodulators to manage Crohn's Disease.

[PMID:35115294] [SUPPORT] Our results show that parenteral use of methotrexate is efficacious in inducing and maintaining remission as a step-up agent in azathioprine refractory Crohn's disease patients. --- Explanation: The study shows the use of methotrexate in patients who are refractory to azathioprine, supporting the statement that these drugs are used to treat Crohn's Disease by mitigating immune response.

[PMID:16245637] [SUPPORT] First line immunosuppressants are Azathioprine and 6-Mercaptopurine while Methotrexate, Infliximab, Mycophenolatmofetil and other compounds represent alternative or rescue medications. --- Explanation: This reference confirms that Azathioprine and Methotrexate are used as immunosuppressants in the treatment of Crohn's Disease.

[PMID:24913384] [SUPPORT] The only other long term disease-modifying options are the immunomodulators, methotrexate, azathioprine and mercaptopurine. --- Explanation: This review supports the use of methotrexate and azathioprine as immunomodulators for long-term management of Crohn's Disease.


MAXO:0000058

[PMID:18034589] [PARTIAL] Infliximab and adalimumab are currently the only biological agents approved for induction and maintenance treatment in adults (infliximab and adalimumab) and children (infliximab) with Crohn's disease. --- Explanation: This reference supports the use of anti-TNF agents (infliximab and adalimumab) for the treatment of moderate to severe Crohn's disease but does not mention vedolizumab directly.

[PMID:26195652] [PARTIAL] Vedolizumab is an integrin-receptor antagonist for the treatment of CD and UC in adults with moderately to severely active disease. --- Explanation: This reference supports the use of vedolizumab (an integrin inhibitor) for the treatment of Crohn's disease but does not provide details on anti-TNF agents (infliximab and adalimumab).

[PMID:26616476] [SUPPORT] Anti-TNF-alpha therapy is a novel approach that has transformed the way moderate-to-severe Crohn's disease (CD) is treated and has significantly improved clinical outcomes of patients. --- Explanation: This reference supports the use of anti-TNF agents for moderate to severe Crohn's disease.


MAXO:0000088

[PMID:19244154] [SUPPORT] Nutrition therapy of Crohn's disease is considered the first-line of treatment for Crohn's disease in children, especially in Europe. --- Explanation: This article supports the use of nutrition therapy as a treatment for managing symptoms and maintaining nutrition in Crohn’s disease.

[PMID:38276922] [SUPPORT] New data in Crohn's disease supports the use of enteral liquid nutrition to help induce remission and correct malnutrition in patients heading for surgery. --- Explanation: This article supports the use of enteral nutrition as an effective therapy to induce remission and manage malnutrition in Crohn's disease.

[PMID:36558412] [SUPPORT] Both under-and over-nutrition are prevalent in patients with Crohn's Disease (CD). --- Explanation: The study highlights the importance of dietary modifications to manage nutritional status in Crohn's disease patients.

[PMID:35595414] [SUPPORT] The primary agents used in the treatment of Crohn's disease are aminosalicylates, corticosteroids, immunomodulators, and biologics. Each agent has different roles in the induction and maintenance of remission of disease. --- Explanation: While this primarily focuses on pharmacologic therapy, it does acknowledge the role of different agents in maintaining remission.

[PMID:22410431] [SUPPORT] Although an elemental diet might lead to disease remission, reintroducing real foods and sustainable diets in patients with Crohn's disease is currently difficult, and would benefit from the sensitivity and rapid feedback provided by the field of nutrigenomics. --- Explanation: This reference suggests that dietary modifications can lead to remission and maintenance of Crohn's disease, validating the role of nutritional therapy.


MAXO:0000004

[PMID:21901520] [SUPPORT] The indications for surgery include the failure of medical management, especially the persistence or worsening of symptoms in spite of proper treatment and complications of the disease process. These complications include intestinal obstruction, intestinal perforation with fistula formation or abscess, free perforation, gastrointestinal bleeding, urologic complications, cancer, and perianal disease. --- Explanation: The excerpt indicates that surgery is reserved for complications such as strictures or fistulas among others, thus supporting the statement.

[PMID:32279173] [SUPPORT] Therefore, current therapy of fibrotic strictures relies mainly on endoscopic and surgical procedures. --- Explanation: The statement mentions surgery for complications like strictures, which is supported by the snippet indicating that fibrotic strictures rely on surgical procedures for treatment.

[PMID:21975159] [SUPPORT] Intestinal resection is almost always needed for the closure of symptomatic non-perianal fistulas. --- Explanation: The statement links surgery to the complication of fistulas, which is supported by the snippet explaining the need for intestinal resection to manage symptomatic non-perianal fistulas.

[PMID:29462390] [SUPPORT] When isolated to the colon, and patients become medically refractory, there are several surgical options - segmental resection, subtotal colectomy with ileorectal anastomosis, or a total proctocolectomy and end ileostomy. Unfortunately, surgery does not cure CD, and, regardless of the extent of bowel removed, recurrence may be seen in the small bowel. --- Explanation: The snippet supports the statement by discussing various surgical options for patients who are medically refractory, involving the removal of affected bowel segments.

[PMID:36926950] [SUPPORT] A partial resection of 3rd and 4th portion of the duodenum and the first loop of jejunum was performed, with duodenojejunal anastomosis. --- Explanation: The provided case demonstrates a scenario where surgery was performed due to refractory disease and complications, supporting the statement.


MAXO:0000058


HGNC.SYMBOL:NOD2

[PMID:29358789] [SUPPORT] BACKGROUND AND OBJECTIVES: Crohn's disease is a multifactorial inflammatory disease affecting mainly the gastrointestinal tract. The genetic factors that are involved in the disease include mainly three mutations of the gene NOD2/CARD15 (R702W, G908R, 3020insC). --- Explanation: This reference states that NOD2 mutations are involved in Crohn's disease, supporting the association as a risk factor.

[PMID:23352252] [SUPPORT] NOD2 gene mutations are associated with several diseases, and some of the mutations are of diagnostic value in Blau disease and NAID... The NOD2 variants located in the leucine-rich repeat (LRR) region are susceptible to Crohn disease. --- Explanation: This reference confirms the association of NOD2 gene mutations with Crohn's disease.

[PMID:16773683] [SUPPORT] Investigations into the inheritance of the three risk alleles R702W, G908R and 1007fsInsC in NOD2 associated with susceptibility to Crohn's disease have demonstrated a remarkable amount of heterogeneity across ethnicities and populations. --- Explanation: This reference clearly establishes the association of specific NOD2 mutations with susceptibility to Crohn's disease.

[PMID:12851870] [SUPPORT] The NOD2 gene, which is strongly associated with susceptibility to Crohn's disease (CD) of the terminal ileum, interacts with bacterial lipopolysaccharide (LPS), inducing cellular activation. --- Explanation: This study supports the role of NOD2 as a genetic risk factor for Crohn's disease.

[PMID:32476786] [SUPPORT] While NOD2 mutations represent well established risk factors of CD, the role of other genes is incompletely understood. --- Explanation: This confirms that NOD2 is a well-established genetic risk factor for Crohn's disease.

[PMID:11385577] [SUPPORT] Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. --- Explanation: This study provides evidence of a specific NOD2 mutation associated with Crohn's disease.

[PMID:17206682] [SUPPORT] The association of NOD2/CARD15 mutations with CD and BS, and possibly also early onset sarcoidosis, suggests a role for the gene in the development of granulomata and granulomatous diseases. --- Explanation: This statement supports the association of NOD2 with Crohn's disease (CD).

[PMID:16987083] [SUPPORT] The mapping to CD of Nod2 variants that alter protein function represents one of the earliest, most well-established, associations in complex genetic disorders. --- Explanation: This reference emphasizes that the NOD2 association with Crohn's disease is well-established.

[PMID:27076762] [SUPPORT] The highest accuracy, AUC of 0.78 was achieved with GRS combining 33 SNPs with optimal sensitivity and specificity of 75.0% and 72.7%, respectively. --- Explanation: This study confirms the role of genetic risk scores including multiple SNP variants for predicting Crohn's disease.


HGNC.SYMBOL:ATG16L1

[PMID:27698206] [SUPPORT] Conclusion In this meta-analysis, the ATG16L1 genotype was significantly associated with the risk of developing Crohn''s disease.

[PMID:25906181] [SUPPORT] single-nucleotide polymorphisms in ATG16L1 ... a key component in the autophagic response to invading pathogens, have been associated with an increased risk of developing Crohn disease.

[PMID:12840668] [NO_EVIDENCE] CARD15 mutations are present in 30-50% of CD patients compared to 7-20% of healthy controls. Interestingly, CD patients often carry mutations on their two chromosomes suggesting a mutation dose effect. --- Explanation: The reference focuses on the association between CARD15 mutations and Crohn’s Disease, with no information regarding ATG16L1.

[PMID:29795570] [NO_EVIDENCE] ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD. --- Explanation: The reference highlights genetic risk factors in NOD2 and LRRK2 for Crohn's Disease, not ATG16L1.

[PMID:27076762] [PARTIAL] We generated genetic risk scores (GRS) based on the number of risk alleles using weighted additive model. Discriminatory accuracy was measured by area under ROC curve (AUC)....The highest accuracy, AUC of 0.78 was achieved with GRS combining 33 SNPs with optimal sensitivity and specificity of 75.0% and 72.7%, respectively. --- Explanation: The study involves identification of SNPs for risk prediction, however ATG16L1 is not mentioned explicitly. Thus, it only partially supports the statement.


HGNC.SYMBOL:IL23R

[PMID:17068223] [SUPPORT] We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. --- Explanation: This study identifies IL23R as a gene significantly associated with Crohn's disease, supporting the statement that IL23R is a genetic risk factor for the condition.

[PMID:24989722] [SUPPORT] We demonstrate a strong increased CD risk for smokers in both datasets (odds ratio 3.77, 95% confidence interval 2.88-4.94), and an additive interaction between IL23R SNPs and cigarette smoking. --- Explanation: This study supports the association between IL23R and Crohn's disease, while also highlighting the interaction between IL23R variants and environmental factors like smoking.


HGNC.SYMBOL:LRRK2


HGNC.SYMBOL:TNFSF15


HGNC.SYMBOL:CARD9


HGNC.SYMBOL:BACH2


HGNC.SYMBOL:TNFAIP3


HGNC.SYMBOL:STAT3


HGNC.SYMBOL:IL10


HGNC.SYMBOL:CD28


HGNC.SYMBOL:EGR2


HGNC.SYMBOL:ETS1


HGNC.SYMBOL:IRF4


HGNC.SYMBOL:IRF8


HGNC.SYMBOL:SATB1


HGNC.SYMBOL:IKZF1


HGNC.SYMBOL:SMAD3


HGNC.SYMBOL:PRDM1


HGNC.SYMBOL:PTPN22


HGNC.SYMBOL:IL21R


ECTO:6000029

[PMID:27016849] [SUPPORT] Smoking increases the risk of complications, recurrences and resort of surgery, corticosteroids or immunosuppressants. --- Explanation: The provided literature clearly states that smoking increases the risk and severity of Crohn's disease, aligning with the statement.

[PMID:31014995] [SUPPORT] We identified 9 factors that increase risk of IBD: smoking (CD)... --- Explanation: The review identifies smoking as a significant environmental risk factor that increases the risk of Crohn's disease.

[PMID:38238335] [SUPPORT] Compared to never smoking, current and previous smoking habits are associated with increased CD (P = 7.09 × 10-10) and UC (P < 2 × 10-16) risk, respectively. --- Explanation: This prospective cohort study finds that both current and previous smoking habits are associated with increased risk of CD, which supports the statement.

[PMID:28838409] [SUPPORT] Understanding the potential environmental risk factors and natural history of CD in a given patient guides the physician when counseling the patient and selecting a treatment strategy. --- Explanation: The review discusses smoking as an important environmental risk factor, thereby supporting the statement.


MONDO:0008283

[PMID:38297356] [SUPPORT] Cronkhite-Canada syndrome (CCS) is a rare, nonhereditary disease characterized by diffuse gastrointestinal polyposis and ectodermal abnormalities. --- Explanation: Defines CCS as characterized by diffuse gastrointestinal polyposis, establishing this as a cardinal defining feature

[PMID:40709433] [SUPPORT] Endoscopic and histopathological examinations revealed diffuse polyposis throughout the gastrointestinal tract, consistent with CCS findings. --- Explanation: Recent case demonstrates diffuse polyposis throughout entire GI tract as diagnostic hallmark of CCS


MONDO:0008283

[PMID:33163187] [SUPPORT] Typical alopecia involves hair loss, but it is not limited to hair; eyebrows and eyelashes can also fall out --- Explanation: Describes the cutaneous manifestation of alopecia as a characteristic feature of Cronkhite-Canada syndrome

[PMID:39470508] [SUPPORT] The primary clinical manifestations of CCS include hair loss, excessive pigmentation of the skin, and malnourishment of fingernails or toenails. --- Explanation: Recent case report confirms hair loss as a primary clinical manifestation of CCS in a 72-year-old female


MONDO:0008283

[PMID:33163187] [SUPPORT] Typical nail changes include thin, soft, triangular nail plates --- Explanation: Characterizes the distinctive nail changes seen in Cronkhite-Canada syndrome

[PMID:39470508] [SUPPORT] The primary clinical manifestations of CCS include hair loss, excessive pigmentation of the skin, and malnourishment of fingernails or toenails. --- Explanation: Recent comprehensive case report documents nail malnourishment as a primary clinical manifestation


MONDO:0008283

[PMID:33163187] [SUPPORT] With regard to skin changes, pigmentation of the skin is a vital sign, such as brown macula or red nonpruritic nodular papules, which can be seen on the scalp, wrist, palms, soles, limbs, face, and chest --- Explanation: Describes the characteristic pattern and appearance of skin hyperpigmentation in Cronkhite-Canada syndrome


MONDO:0008283

[PMID:33163187] [SUPPORT] Typical symptoms of CCS include hypogeusia, diarrhea, abdominal pain, alopecia, skin pigmentation, onychodystrophy, and even onychomadesis --- Explanation: Establishes diarrhea as a typical feature of Cronkhite-Canada syndrome presentation

[PMID:39470508] [SUPPORT] Other notable symptoms include weight loss, protein-losing enteropathy, diarrhea, abdominal pain, nausea, vomiting, taste abnormalities, and atrophic glossitis --- Explanation: Recent comprehensive review confirms diarrhea as a notable feature of CCS presentation alongside weight loss and protein-losing enteropathy


MONDO:0008283

[PMID:33163187] [SUPPORT] The prognosis of CCS is poor, with a 5-year mortality rate of 55% --- Explanation: Indicates severe complications from protein-losing enteropathy and malnutrition are major causes of morbidity and mortality

[PMID:39470508] [SUPPORT] Other notable symptoms include weight loss, protein-losing enteropathy, diarrhea, abdominal pain, nausea, vomiting, taste abnormalities, and atrophic glossitis, which predominantly occur in middle-aged and older males. --- Explanation: Confirms protein-losing enteropathy as a notable and frequently occurring symptom in CCS, particularly in middle-aged and older patients


MONDO:0008283

[PMID:33163187] [INDIRECT EVIDENCE] [SUPPORT] CCS is typically characterized by gastrointestinal symptoms, such as diarrhea and skin changes (e.g. alopecia, pigmentation, and nail atrophy). Endoscopic features include diffuse polyps throughout the entire gastrointestinal tract, except for the esophagus. --- Explanation: Describes the characteristic clinical presentation and gastrointestinal involvement in Cronkhite-Canada syndrome

[PMID:39470508] [INDIRECT EVIDENCE] [SUPPORT] CCS is characterized by an extremely rare, nonfamilial hamartomatous polyposis syndrome, in which polyps are distributed in the stomach and colon (90%), small intestine(80%), and rectum (67%), while sparing the esophagus. --- Explanation: Comprehensive case series quantifies the distribution and frequency of polyp involvement across different GI segments


MONDO:0008283


MONDO:0008283

[PMID:33163187] [INDIRECT EVIDENCE] [SUPPORT] IgG4-positive plasma-cell infiltration was also found in CCS polyps --- Explanation: Establishes IgG4-positive plasma cell infiltration as a key pathogenic feature of Cronkhite-Canada syndrome

[PMID:39470508] [INDIRECT EVIDENCE] [SUPPORT] In this case, from the lower esophageal sphincter to the rectum, there is an increasing trend of eosinophil and mast cell infiltration. These lesions can cause a positive IgG result. --- Explanation: Demonstrates the progressive eosinophil and mast cell infiltration along the GI tract with IgG involvement in CCS pathology


MONDO:0008283

[PMID:33163187] [INDIRECT EVIDENCE] [SUPPORT] The prognosis of CCS is poor, with a 5-year mortality rate of 55% --- Explanation: Indicates the severe clinical consequences of CCS including complications from protein-losing enteropathy

[PMID:39470508] [INDIRECT EVIDENCE] [SUPPORT] The primary distinct features of this syndrome include ectodermal abnormalities and diffuse gastrointestinal polyp changes accompanied by protein loss. --- Explanation: Establishes protein loss as a primary pathogenic feature accompanying the GI polyp changes in CCS


MONDO:0008283

[PMID:33163187] [INDIRECT EVIDENCE] [SUPPORT] 54% of patients with CCS had Hp infection and some studies noted that CCS was alleviated after Hp eradication --- Explanation: Documents the association between H. pylori infection and CCS with therapeutic improvement after eradication

[PMID:39470508] [INDIRECT EVIDENCE] [SUPPORT] Pathological analysis indicates that the extent and severity of lesions in the middle and lower gastrointestinal tract are more substantial than in the upper tract. --- Explanation: Recent case demonstrates the gradual pattern of GI tract involvement that may reflect H. pylori-associated inflammation patterns


MAXO:0000640

[PMID:33163187] [SUPPORT] Hormone therapy is the main treatment and prednisone is the major drug. Over 85% of patients responded to a dosage of >30 mg/d --- Explanation: Establishes corticosteroids as first-line therapy with high response rates in Cronkhite-Canada syndrome

[PMID:39470508] [SUPPORT] Hormone therapy has demonstrated significant efficacy in treating this disease. Early treatment and regular follow-up for this disease can reduce the risk of cancerous changes and related complications. --- Explanation: Recent case report confirms hormone therapy efficacy and emphasizes importance of early treatment in preventing cancer progression

[PMID:32459145] [SUPPORT] Glucocorticoid dosage is generally considered to be based on body weight (1 mg/kg); its therapeutic mechanism may involve reduction of gastrointestinal inflammation and inhibition of autoimmune responses. --- Explanation: Detailed case report establishes dosing rationale and mechanism of action for glucocorticoid therapy in CCS

[PMID:36781513] [SUPPORT] All patients received an initial prednisone dose equivalence of 30-80 mg daily, and five patients required steroids at the time of the last follow-up. --- Explanation: Large cohort study confirms prednisone dosing range and documents sustained steroid requirement in subset of patients for long-term disease control

[PMID:34002159] [SUPPORT] It is necessary to extend the duration of prednisone maintenance therapy for CCS. Prednisone is still effective when readministered after relapse. --- Explanation: Case report demonstrates importance of extended maintenance therapy and confirms effectiveness of steroid retreatment after relapse