MONDO:0008318

[DOI:10.1101/2024.01.26.577324] [INDIRECT EVIDENCE] [SUPPORT] Our findings revealed that AKT overactivation in these organoids resulted in smaller sizes yet increased vascular connectivity, although with less stable connections. --- Explanation: AKT overactivation is linked to unstable vascular connections.

[DOI:10.1101/2024.01.26.577324] [INDIRECT EVIDENCE] [SUPPORT] Additionally, a notable increase in dysfunctional PDGFRβ + mural cells, impaired in matrix secretion, was observed in these AKT-overactivated organoids. --- Explanation: This supports mural cell dysfunction as part of the vascular phenotype.


MONDO:0008318


MAXO:0000058

[DOI:10.1038/srep17162] [SUPPORT] ARQ 092 reduced phosphorylation of AKT and downstream targets of AKT in a concentration-dependent manner in as little as two hours. --- Explanation: This shows AKT pathway suppression by ARQ 092 in Proteus syndrome samples.

[DOI:10.1101/mcs.a006134] [SUPPORT] The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi. --- Explanation: This case report describes clinical benefit with miransertib (ARQ 092).


MAXO:0000004

[DOI:10.1055/a-2300-7002] [SUPPORT] We report a case of PS in a two-year-old female patient with the following clinical features: unilateral overgrowth of connective tissue in the right buttock and right foot, where multiple surgeries were performed to achieve a desirable aesthetic outcome and ensure psychological comfort of the young patient. --- Explanation: This case report documents surgical intervention for overgrowth management.


HGNC.SYMBOL:AKT1

[DOI:10.1038/srep17162] [SUPPORT] A somatic activating mutation in AKT1, c.49G>A, pGlu17Lys, that results in elevated AKT signaling in mutation-positive cells, is responsible for the mosaic overgrowth condition, Proteus syndrome. --- Explanation: This identifies the causative somatic AKT1 variant.

[DOI:10.1093/hmg/ddz116] [SUPPORT] Proteus syndrome is a mosaic, progressive overgrowth disorder caused by a somatic activating variant c.49G > A p.(E17K) in AKT1. --- Explanation: This independently confirms the AKT1 p.E17K mosaic variant as the cause.


MONDO:0026045

[PMID:38345154] [SUPPORT] intensely pruritic nodules on the skin. --- Explanation: The abstract describes PN as intensely pruritic.


MONDO:0026045

[PMID:38345154] [SUPPORT] intensely pruritic nodules on the skin. --- Explanation: The abstract states that PN is characterized by nodules on the skin.


MONDO:0019992

[PMID:37014531] [SUPPORT] It is characterized by hypocalcemia, hyperphosphatemia, and an elevated parathyroid hormone concentration secondary to the resistance of target tissues to the biological actions of parathyroid hormone. --- Explanation: Confirms hypocalcemia as a defining biochemical consequence of PHP.


MONDO:0019992

[PMID:37014531] [SUPPORT] It is characterized by hypocalcemia, hyperphosphatemia, and an elevated parathyroid hormone concentration secondary to the resistance of target tissues to the biological actions of parathyroid hormone. --- Explanation: Confirms hyperphosphatemia as part of the hallmark PHP biochemical triad.


MONDO:0019992

[PMID:35410271] [SUPPORT] Laboratory assessments of the patient revealed hypokalemia, hypocalcemia and hyperphosphatemia despite elevated PTH levels. --- Explanation: Supports elevation of PTH despite biochemical hypocalcemia-hyperphosphatemia.


MONDO:0019992

[PMID:35410271] [SUPPORT] Seven months after delivery, she experienced tetany and dysphonia with diarrhea. --- Explanation: Documents tetany as an acute symptomatic manifestation in PHP.


MONDO:0019992

[PMID:38423572] [SUPPORT] We describe a case in which epileptic seizures and abnormalities in dental development were the main clinical manifestation of PHP type 1B. --- Explanation: Supports seizures as a clinically important presentation in PHP1B.


MONDO:0019992

[PMID:29959430] [SUPPORT] resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. --- Explanation: Consensus statement lists brachydactyly among major diagnostic criteria.


MONDO:0019992

[PMID:29959430] [SUPPORT] include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications --- Explanation: Identifies short stature as part of the core physical phenotype in PHP-related disorders.


MONDO:0019992

[PMID:38103632] [SUPPORT] Genetic or epigenetic alterations in GNAS are known to cause pseudohypoparathyroidism in its different subtypes and have been recently associated with isolated, early-onset, severe obesity. --- Explanation: Supports mechanistic and clinical linkage between GNAS defects and early-onset obesity.


MONDO:0019992

[PMID:29959430] [SUPPORT] subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. --- Explanation: Consensus guidance highlights subcutaneous ectopic ossifications as a monitored feature.


MONDO:0019992

[PMID:29959430] [SUPPORT] specific features, such as PTH resistance, TSH resistance, growth hormone deficiency --- Explanation: TSH resistance provides mechanistic support for hypothyroid manifestations in PHP.


MONDO:0019992

[PMID:29959430] [SUPPORT] subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. --- Explanation: Neurocognitive impairment in consensus guidance supports developmental and cognitive phenotype burden.


MONDO:0019992

[PMID:40972900] [INDIRECT EVIDENCE] [SUPPORT] Thus, genomic imprinting plays a key role in the phenotypes associated with GNAS alterations. --- Explanation: Establishes imprinting as the upstream mechanism determining subtype-specific manifestations.

[PMID:25905388] [INDIRECT EVIDENCE] [SUPPORT] PHP1A and PHP1B are caused by maternally-inherited changes at the imprinted GNAS complex gene --- Explanation: Supports maternal-allele GNAS alterations as a core etiologic mechanism.


MONDO:0019992


MONDO:0019992

[PMID:40972900] [INDIRECT EVIDENCE] [SUPPORT] including the proximal renal tubule, where PTH exerts critical actions. --- Explanation: Identifies proximal renal tubule as the key imprinting-sensitive site for PTH resistance.

[PMID:37014531] [INDIRECT EVIDENCE] [SUPPORT] It is characterized by hypocalcemia, hyperphosphatemia, and an elevated parathyroid hormone concentration secondary to the resistance of target tissues to the biological actions of parathyroid hormone. --- Explanation: Confirms the biochemical triad resulting from end-organ PTH resistance.


MONDO:0019992

[PMID:35410271] [INDIRECT EVIDENCE] [SUPPORT] Laboratory assessments of the patient revealed hypokalemia, hypocalcemia and hyperphosphatemia despite elevated PTH levels. --- Explanation: Demonstrates clinically relevant mineral imbalance expected from PTH resistance.


MONDO:0019992

[PMID:29959430] [INDIRECT EVIDENCE] [SUPPORT] specific features, such as PTH resistance, TSH resistance, growth hormone deficiency --- Explanation: Supports that endocrine resistance in PHP commonly extends beyond PTH signaling.


MONDO:0019992

[PMID:29959430] [INDIRECT EVIDENCE] [SUPPORT] resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. --- Explanation: Defines the core AHO-associated developmental phenotype cluster.

[PMID:40972900] [INDIRECT EVIDENCE] [SUPPORT] While maternal mutations result in PHP type 1A, which consists of PTH resistance and AHO, paternal mutations lead to pseudo-pseudohypoparathyroidism (PPHP), that is, AHO without hormone resistance. --- Explanation: Supports parent-of-origin partitioning of AHO features versus hormone resistance.


hgnc:4392

[PMID:37014531] [SUPPORT] Pseudohypoparathyroidism (PHP) is a disorder caused by mutations and/or epigenetic changes at the complex GNAS locus. --- Explanation: Supports both genetic and epigenetic GNAS mechanisms in disease causation.


MONDO:0005083

[PMID:15708928] [SUPPORT] most commonly the disease presents as chronic, symmetrical, erythematous, scaling papules and plaques. --- Explanation: Erythematous plaques are the most common clinical presentation of psoriasis.


MONDO:0005083

[PMID:39576422] [NO_EVIDENCE] Psoriasis represents a chronic autoimmune skin condition defined by various clinical forms, including inverse, erythrodermic, pustular, guttate, plaque types. --- Explanation: The various clinical forms of psoriasis, particularly plaque type, are characterized by silvery scales resulting from rapid keratinocyte turnover and incomplete differentiation.


MONDO:0005083

[PMID:11069504] [SUPPORT] Generalized pruritus was a feature of psoriasis in 84% of the patients. --- Explanation: Pruritus is a common and significant symptom in psoriasis, affecting the majority of patients and impacting quality of life.


MONDO:0005083

[PMID:26131859] [SUPPORT] Nail psoriasis is estimated in 50% of patients with psoriasis, and in the presence of joint involvement, it can reach 80%. --- Explanation: Nail involvement is common in psoriasis patients and may include pitting, onycholysis, and subungual hyperkeratosis.


MONDO:0005083

[PMID:29928910] [SUPPORT] We found that 1 in 4 patients with psoriasis have PsA. --- Explanation: Psoriatic arthritis is a common comorbidity in psoriasis patients, affecting approximately 20-25% based on this meta-analysis.


MONDO:0005083

[PMID:38686385] [INDIRECT EVIDENCE] [PARTIAL] Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. --- Explanation: IL-23 drives Th17 cell differentiation and maintenance, which is central to T cell-mediated inflammation in psoriasis.

[PMID:39337637] [INDIRECT EVIDENCE] [PARTIAL] Current research efforts to better understand skin disease have focused on examining the role of molecular processes at several stages of the inflammatory response such as the dysregulation of innate immunity sensors, disruption of both transcriptional and post-transcriptional regulation, and crosstalk between immune and neuronal processes (neuro-immune crosstalk). --- Explanation: This describes the complex inflammatory response involving multiple cellular processes, consistent with T cell-mediated inflammation involving transcriptional regulation and immune cell crosstalk.


MONDO:0005083


MONDO:0005083

[PMID:39337637] [INDIRECT EVIDENCE] [NO_EVIDENCE] Many skin diseases begin with inflammatory changes on a molecular level. --- Explanation: Inflammatory changes at the molecular level drive keratinocyte hyperproliferation in psoriasis, linking inflammation to cellular proliferation.

[PMID:39576422] [INDIRECT EVIDENCE] [NO_EVIDENCE] Psoriasis represents a chronic autoimmune skin condition defined by various clinical forms, including inverse, erythrodermic, pustular, guttate, plaque types. --- Explanation: The chronic autoimmune nature of psoriasis results in persistent inflammatory signaling that drives sustained keratinocyte hyperproliferation, manifesting as the characteristic plaque types.


MONDO:0005083

[PMID:38686385] [INDIRECT EVIDENCE] [PARTIAL] We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases. --- Explanation: Dendritic cells are the primary producers of IL-23, which is central to psoriasis pathophysiology. This evidence supports the critical role of dendritic cell activation in initiating the inflammatory cascade through IL-23 production.

[PMID:39337637] [INDIRECT EVIDENCE] [NO_EVIDENCE] Current research efforts to better understand skin disease have focused on examining the role of molecular processes at several stages of the inflammatory response such as the dysregulation of innate immunity sensors, disruption of both transcriptional and post-transcriptional regulation, and crosstalk between immune and neuronal processes (neuro-immune crosstalk). --- Explanation: Dendritic cells act as innate immunity sensors and initiate the inflammatory response through antigen presentation and cytokine production, representing the dysregulation of innate immunity sensors described here.


MONDO:0005083

[PMID:38686385] [INDIRECT EVIDENCE] [PARTIAL] Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. --- Explanation: This confirms IL-23 as the hierarchically dominant regulatory cytokine in psoriasis, supporting its central role in the IL-23/IL-17 axis and why it is the major therapeutic target.

[PMID:39337637] [INDIRECT EVIDENCE] [NO_EVIDENCE] Many skin diseases begin with inflammatory changes on a molecular level. --- Explanation: This establishes that inflammatory molecular mechanisms are fundamental to skin disease pathogenesis, consistent with the IL-23/IL-17 inflammatory axis driving psoriasis.


MAXO:0000058


MAXO:0000058

[PMID:38686385] [PARTIAL] We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases. --- Explanation: This paper reviews the therapeutic effect of IL-23 inhibition in treating psoriasis and other immune-mediated inflammatory diseases, supporting the use of IL-23 inhibitors like guselkumab and risankizumab.


MAXO:0000058

[PMID:38686385] [PARTIAL] Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. --- Explanation: Ustekinumab targets the p40 subunit shared by IL-12 and IL-23. Given IL-23's hierarchically dominant role, blocking this shared subunit provides therapeutic benefit in psoriasis.


HGNC.SYMBOL:HLA-C*06:02


HGNC.SYMBOL:IL12B

[PMID:38686385] [NO_EVIDENCE] Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. --- Explanation: IL12B encodes the p40 subunit shared by IL-12 and IL-23. Given IL-23's hierarchically dominant role in psoriasis, genetic variants in IL12B that affect IL-23 levels represent important risk factors.


HGNC.SYMBOL:IL23R

[PMID:38686385] [NO_EVIDENCE] We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases. --- Explanation: IL23R encodes the IL-23 receptor, and genetic variants affecting IL-23 signaling are risk factors for psoriasis given the central role of this pathway.


HGNC.SYMBOL:TNFAIP3


HGNC.SYMBOL:CARD14


HGNC.SYMBOL:BACH2


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:REL


HGNC.SYMBOL:PRDM1


HGNC.SYMBOL:PTPN22


MONDO:0011849

[PMID:36902329] [PARTIAL] Psoriatic arthritis (PsA), a heterogeneous chronic inflammatory immune-mediated disease characterized by musculoskeletal inflammation (arthritis, enthesitis, spondylitis, and dactylitis), generally occurs in patients with psoriasis. --- Explanation: The abstract explicitly lists arthritis as a key manifestation.


MONDO:0011849

[PMID:36902329] [PARTIAL] Psoriatic arthritis (PsA), a heterogeneous chronic inflammatory immune-mediated disease characterized by musculoskeletal inflammation (arthritis, enthesitis, spondylitis, and dactylitis), generally occurs in patients with psoriasis. --- Explanation: Enthesitis is listed among the musculoskeletal manifestations of PsA.


MONDO:0011849

[PMID:36902329] [PARTIAL] Psoriatic arthritis (PsA), a heterogeneous chronic inflammatory immune-mediated disease characterized by musculoskeletal inflammation (arthritis, enthesitis, spondylitis, and dactylitis), generally occurs in patients with psoriasis. --- Explanation: Spondylitis is listed among the musculoskeletal manifestations of PsA.


MONDO:0011849

[PMID:36902329] [SUPPORT] PsA is also associated with uveitis and inflammatory bowel disease (Crohn's disease and ulcerative colitis). --- Explanation: The abstract notes uveitis as an associated manifestation of PsA.


MONDO:0011849

[PMID:36902329] [INDIRECT EVIDENCE] [PARTIAL] Research has identified several immune-inflammatory pathways defined by cytokines (IL-23/IL-17, TNF), leading to the development of efficacious therapeutic targets. --- Explanation: The abstract highlights cytokine pathways as central inflammatory drivers in PsA.


MAXO:0000058

[PMID:36902329] [SUPPORT] Research has identified several immune-inflammatory pathways defined by cytokines (IL-23/IL-17, TNF), leading to the development of efficacious therapeutic targets. --- Explanation: The abstract links cytokine pathways to targeted therapies in psoriatic arthritis.


MONDO:0005149


MAXO:0000058


MAXO:0000503


MAXO:0000181


HGNC.SYMBOL:BMPR2


HGNC.SYMBOL:SMAD9


HGNC.SYMBOL:ACVRL1


HGNC.SYMBOL:ENG


HGNC.SYMBOL:EIF2AK4


HGNC.SYMBOL:KCNK3


HGNC.SYMBOL:TBX4


HGNC.SYMBOL:SOX17


HGNC.SYMBOL:CAV1


MONDO:0009940

[PMID:8703060] [SUPPORT] an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature --- Explanation: Osteosclerosis is a defining feature of pycnodysostosis.


MONDO:0009940

[PMID:21569238] [SUPPORT] Skeletal abnormalities, including short stature, an increase in bone density with pathologic fractures, and open fontanels and sutures, are the typical phenotypes of pycnodysostosis --- Explanation: Short stature listed as a typical pycnodysostosis phenotype.


MONDO:0009940

[PMID:21569238] [SUPPORT] short stature, an increase in bone density with pathologic fractures --- Explanation: Pathologic fractures are a typical feature of pycnodysostosis.


MONDO:0009940

[PMID:21569238] [SUPPORT] open fontanels and sutures, are the typical phenotypes of pycnodysostosis --- Explanation: Open fontanelles and sutures are a characteristic diagnostic feature.


MONDO:0009940

[PMID:8703060] [INDIRECT EVIDENCE] [SUPPORT] pycnodysostosis results from gene defects in a lysosomal protease with highest expression in osteoclasts --- Explanation: Identifies cathepsin K as an osteoclast-specific lysosomal protease causing pycnodysostosis.

[PMID:21569238] [INDIRECT EVIDENCE] [SUPPORT] CTSK mutations result in total loss or inactivity of the CTSK protein, which causes abnormal degradation of bone matrix proteins such as type I collagen --- Explanation: Confirms that CTSK mutations abolish collagen degradation capacity.

[PMID:21569238] [INDIRECT EVIDENCE] [SUPPORT] The hot mutation spots are found in exons 6 and 7 --- Explanation: Identifies mutational hotspots in the CTSK gene.


MONDO:0009940

[PMID:8703060] [INDIRECT EVIDENCE] [SUPPORT] cathepsin K is a major protease in bone resorption --- Explanation: Establishes cathepsin K as the primary bone matrix-degrading enzyme.


MONDO:0009940


MAXO:0000950


MAXO:0000079


HGNC.SYMBOL:CTSK Mutations

[PMID:8703060] [SUPPORT] Nonsense, missense, and stop codon mutations in the gene encoding cathepsin K were identified in patients --- Explanation: Identifies the range of CTSK mutation types in pycnodysostosis.

[PMID:21569238] [SUPPORT] Thirty three different CTSK mutations have been found in 59 unrelated pycnodysostosis families --- Explanation: Comprehensive catalog of 33 mutations in 59 families.


MONDO:0005075


MAXO:0000004


MAXO:0000014


MAXO:0000058


NCIT:C134987


NCIT:C132295


CHEBI:85994


HGNC.SYMBOL:RET

[PMID:39502057] [PARTIAL] The common gene mutations in PTC include BRAF V600E,RET/PTC rearrangement,and RAS mutations. --- Explanation: Supports RET/PTC rearrangements as common mutations in papillary thyroid carcinoma.


MONDO:0005075

[PMID:21221869] [PARTIAL] Papillary thyroid carcinomas are the most common thyroid cancers --- Explanation: Abstract notes papillary thyroid carcinoma as the most common thyroid cancer.


MONDO:0005061


MONDO:0005061

[PMID:38110308] [INDIRECT EVIDENCE] [PARTIAL] Nearly 1% to 2% of NSCLCs harbor RET fusions, and this patient population may not respond well to traditional treatments like chemotherapy or radiation therapy. --- Explanation: Supports the presence of RET fusions in a subset of NSCLC.


CHEBI:72317


MAXO:0000647


HGNC.SYMBOL:RET

[PMID:35220468] [PARTIAL] Approximately 1-2% of non-small cell lung cancer (NSCLC) patients harbor RET (rearranged during transfection) fusions. --- Explanation: Abstract reports the frequency of RET fusions in NSCLC.


HGNC.SYMBOL:KIF5B


MONDO:0005061

[PMID:32657049] [PARTIAL] Of 256 patients with NSCLC, 219 were adenocarcinoma --- Explanation: Abstract reports a NSCLC cohort dominated by adenocarcinoma.


MONDO:0005061

[PMID:31720561] [INDIRECT EVIDENCE] [PARTIAL] ROS1 gene fusions account for approximately 1-2% of all cases of non-small cell lung cancer (NSCLC). --- Explanation: This abstract establishes that ROS1 fusions define a small NSCLC subset, supporting the ROS1 gene rearrangement mechanism.


CHEBI:64310


CHEBI:195558


CHEBI:143117


MAXO:0000058


CHEBI:229220


HGNC.SYMBOL:ROS1

[PMID:32327173] [PARTIAL] ROS1-rearranged non-small cell lung cancer (NSCLC) makes up approximately 1% to 2% of all NSCLC, --- Explanation: Abstract reports ROS1-rearranged NSCLC accounts for about 1-2% of cases.


HGNC.SYMBOL:CD74


MONDO:0100437

[PMID:26843488] [SUPPORT] Symptoms of nyctalopia typically begin in childhood, with increasing loss of peripheral visual field during teenage years, and progressive central visual loss during the second to fourth decade of life. --- Explanation: This review supports childhood night blindness as a hallmark presenting phenotype of rod-predominant RPGR disease.


MONDO:0100437

[PMID:26843488] [SUPPORT] Symptoms of nyctalopia typically begin in childhood, with increasing loss of peripheral visual field during teenage years, and progressive central visual loss during the second to fourth decade of life. --- Explanation: This review supports progressive peripheral field constriction as a core RPGR-RP phenotype.


MONDO:0100437

[PMID:29528978] [SUPPORT] The probability of being blind (best-corrected visual acuity <0.05) at the age of 40 was 20% and 55% in patients with RP and COD/CORD, respectively. --- Explanation: This cohort shows severe acuity loss across RPGR disease and earlier blindness risk in cone-predominant branches.

[PMID:35806195] [SUPPORT] When analyzing the longitudinal data, a progressive decline in visual acuity (VA) was noted, with more than 60% of the patients reaching VA ≥ 1 LogMar in the best eye after the fifth decade of life. --- Explanation: This natural-history study directly supports progressive acuity decline in RPGR cone and cone-rod disease.


MONDO:0100437

[PMID:29528978] [SUPPORT] RPGR-ORF15 mutations were associated with high myopia (P = 0.01), which led to a faster best-corrected visual acuity decline in patients with RP (P < 0.001) and COD/CORD (P = 0.03). --- Explanation: This cohort supports high myopia as an important RPGR-associated ophthalmic feature and severity modifier.


MONDO:0100437

[PMID:26843488] [INDIRECT EVIDENCE] [SUPPORT] RPGR is involved in ciliary function, with ciliary dysfunction now recognised as the mechanism underlying a large proportion of inherited retinal disease. --- Explanation: This review identifies ciliary dysfunction as the shared proximal RPGR disease mechanism.

[PMID:27493202] [INDIRECT EVIDENCE] [SUPPORT] Ablation of PDE6D blocked ciliary targeting of RPGR. --- Explanation: This ciliary-targeting study shows that RPGR itself depends on intact ciliary trafficking machinery.


MONDO:0100437


MONDO:0100437

[PMID:26936822] [INDIRECT EVIDENCE] [SUPPORT] We also observed disorganized photoreceptor outer-segment morphology and defective trafficking of opsins in the Rpgrko/Y::Cep290rd16/+ mice. --- Explanation: This model-organism study supports outer-segment failure as a direct consequence of RPGR disruption.


MONDO:0100437

[PMID:29528978] [INDIRECT EVIDENCE] [SUPPORT] RPGR-ORF15 mutations were associated with COD/CORD and with a more severe phenotype in RP. --- Explanation: This cohort supports subtype divergence linked to RPGRORF15 variation.

[PMID:35806195] [INDIRECT EVIDENCE] [SUPPORT] All were located in the 3' half of the RPGRORF15 transcript. --- Explanation: This cone/cone-rod series localizes cone-biased disease to the 3' half of RPGRORF15.


MONDO:0100437

[PMID:32012938] [INDIRECT EVIDENCE] [SUPPORT] A histological examination of the donor eye showed disruption of retinal topology and stratification, with a more severe loss found in the peripheral regions. Reactive gliosis was seen in the inner layers of all regions. --- Explanation: Human donor-eye histopathology supports end-stage photoreceptor loss with secondary retinal remodeling.


hgnc:10295

[PMID:26843488] [SUPPORT] Retinitis pigmentosa GTPase regulator (RPGR) gene sequence variants account for the vast majority of X linked retinitis pigmentosa (RP), which is one of the most severe forms of RP. --- Explanation: This review supports RPGR as the principal causal gene in the X-linked RP branch of the family.

[PMID:35806195] [SUPPORT] Variants in the X-linked retinitis pigmentosa GTPase regulator gene (RPGR) and, specifically, in its retinal opening reading frame-15 isoform (RPGRORF15) may cause rod-cone (RCD), cone, and cone-rod dystrophies (CDs and CRDs). --- Explanation: This natural-history study supports RPGR, especially RPGRORF15, as the shared causal gene across multiple subtype branches.


MONDO:0100437

[PMID:26843488] [SUPPORT] Retinitis pigmentosa GTPase regulator (RPGR) gene sequence variants account for the vast majority of X linked retinitis pigmentosa (RP), which is one of the most severe forms of RP. --- Explanation: This review supports the canonical X-linked inheritance pattern of RPGR retinal disease.

[PMID:37541846] [SUPPORT] In summary, our data suggest that skewed X-chromosomal inactivation is an important factor that determines the disease manifestation of RP among female carriers of pathogenic sequence alterations in the RPGR gene. --- Explanation: This family and cell-based study supports X-inactivation as a modifier of female carrier manifestation.


MONDO:0017990

[PMID:37558300] [SUPPORT] characterized by bidirectional or polymorphic ventricular arrhythmia provoked by exercise or emotion --- Explanation: Bidirectional VT is the hallmark arrhythmia of CPVT.


MONDO:0017990

[PMID:32115705] [SUPPORT] If patients on maximally tolerated beta-blocker therapy continue to have syncope or recurrent sustained VT, treatment should be intensified --- Explanation: Syncope is recognized as a key clinical presentation in CPVT patients, referenced in treatment escalation guidelines.


MONDO:0017990

[PMID:39835466] [SUPPORT] Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating heritable channelopathy that can lead to sudden cardiac death in children and young adults --- Explanation: Sudden cardiac death is a defining risk of CPVT.


MONDO:0017990

[PMID:32115705] [SUPPORT] Symptoms range from palpitations to cardiac arrest --- Explanation: Palpitations are part of the CPVT symptom spectrum.


MONDO:0017990

[PMID:32115705] [SUPPORT] CPVT is a stress-induced cardiac channelopathy that has a high mortality in untreated patients --- Explanation: Ventricular fibrillation is the mechanism of sudden death in CPVT.


MONDO:0017990

[PMID:32115705] [SUPPORT] mortality rates between 30 and 50% in untreated individuals by age 40 --- Explanation: Cardiac arrest is a major cause of mortality in CPVT.


MONDO:0017990

[PMID:39835466] [SUPPORT] there is an increasing recognition of the extra-cardiac manifestations such as epilepsy, neurodevelopmental delay, and glucose homeostasis abnormalities in RyR2 variant carriers --- Explanation: Epilepsy is an emerging extra-cardiac manifestation of RYR2 variants.


MONDO:0017990

[PMID:35222090] [INDIRECT EVIDENCE] [SUPPORT] The most common cellular phenotype in CPVT is higher than normal cytoplasmic Ca2+ concentrations during diastole due to Ca2+ leak from the SR through mutant RyR2 --- Explanation: Establishes that diastolic SR calcium leak through mutant RyR2 is the hallmark cellular phenotype in CPVT.

[PMID:32115705] [INDIRECT EVIDENCE] [SUPPORT] the deadly arrhythmias are caused by unregulated 'pathological' calcium release from the sarcoplasmic reticulum (SR), the major calcium storage organelle in striated muscle --- Explanation: Confirms that pathological SR calcium release is the mechanistic basis of CPVT arrhythmias.


MONDO:0017990


MONDO:0017990

[PMID:35222090] [INDIRECT EVIDENCE] [SUPPORT] Arrhythmias are triggered when the surface membrane sodium calcium exchanger (NCX) lowers cytoplasmic Ca2+ by importing 3 Na+ ions to extrude one Ca2+ ion. The Na+ influx leads to delayed after depolarizations (DADs) which trigger arrhythmia when reaching action potential threshold. --- Explanation: Describes the DAD mechanism linking calcium overload to triggered arrhythmias.


MAXO:0000058

[PMID:26432584] [SUPPORT] The incidence and severity of ventricular arrhythmias decreased during treatment with nadolol compared with during treatment with β1-selective β-blockers --- Explanation: Demonstrates nadolol superiority over selective beta-blockers in CPVT.


MAXO:0000058

[PMID:19835880] [SUPPORT] flecainide significantly reduced spark amplitude and spark width, resulting in a 40% reduction in spark mass --- Explanation: Demonstrates the mechanism by which flecainide suppresses arrhythmogenic calcium waves in isolated cardiomyocytes from a CPVT mouse model.

[PMID:19835880] [SUPPORT] we recently found that the drug flecainide inhibits RyR2 channels and prevents CPVT in mice and humans --- Explanation: Establishes flecainide as an effective CPVT therapy through RyR2 channel inhibition.


MAXO:0000004

[PMID:39835466] [SUPPORT] Early genetic testing and personalized treatment, including beta-blockers, flecainide, and ICDs, is important in improving outcomes --- Explanation: ICDs are part of the standard CPVT management toolkit.


MAXO:0000950

[PMID:37558300] [SUPPORT] characterized by bidirectional or polymorphic ventricular arrhythmia provoked by exercise or emotion --- Explanation: Exercise provocation of arrhythmias is the basis for activity restriction recommendations.


hgnc:10484

[PMID:32115705] [SUPPORT] Gain-of-function mutations in the RYR2 gene are found in about 95% of patients with a genetically confirmed diagnosis of CPVT --- Explanation: Establishes that RYR2 gain-of-function mutations account for the vast majority (~95%) of genetically confirmed CPVT cases.

[PMID:35222090] [SUPPORT] Mutations in proteins involved in Ca2+ signaling can lead to catecholaminergic polymorphic ventricular tachycardia (CPVT) --- Explanation: Confirms that calcium signalling protein mutations (primarily RYR2) cause CPVT.


MONDO:0017990

[PMID:32115705] [SUPPORT] Gain-of-function mutations in the RYR2 gene are found in about 95% of patients with a genetically confirmed diagnosis of CPVT (Pérez-Riera et al. 2018) and are designated as CPVT type 1 (CPVT1). CPVT1 is autosomal-dominant --- Explanation: Directly states that RYR2-associated CPVT (CPVT1) follows autosomal dominant inheritance.


MONDO:0019173

[PMID:12144896] [SUPPORT] Rabies is an acute, progressive, incurable viral encephalitis. --- Explanation: Rabies presents as infectious encephalitis.


MAXO:0001017

[PMID:12144896] [SUPPORT] Prophylaxis encompasses thorough wound treatment, vaccine administration, and inoculation of rabies immunoglobulin. --- Explanation: The abstract describes vaccine administration for prophylaxis.


MAXO:0000058

[PMID:12144896] [SUPPORT] Prophylaxis encompasses thorough wound treatment, vaccine administration, and inoculation of rabies immunoglobulin. --- Explanation: The abstract includes rabies immunoglobulin as part of prophylaxis.


NCBITaxon:11292

[PMID:12144896] [SUPPORT] The causative agents are neurotropic RNA viruses in the family Rhabdoviridae, genus Lyssavirus. --- Explanation: The abstract identifies lyssaviruses as the causative agents.


MONDO:0008364

[PMID:25770637] [SUPPORT] Raynaud syndrome (RS) was first described by the French physician Maurice Raynaud in 1862 with the characteristic tricolor change featuring pallor (ischemic phase), cyanosis (deoxygenation phase), and erythema (reperfusion phase) induced by cold or stress. --- Explanation: Classic triphasic color change as the hallmark clinical feature.

[PMID:24418302] [SUPPORT] Raynaud's phenomenon (RP) is a well defined clinical syndrome characterized by recurrent episodes of digital vasospasm triggered by exposure to physical/chemical or emotional stress. --- Explanation: Defines RP as a clinical syndrome of recurrent digital vasospasm.


MONDO:0008364

[PMID:39040029] [SUPPORT] Pallor indicates reduced blood flow due to oxygen deprivation, while erythema appears as reperfusion. --- Explanation: Describes the color change phases including cyanosis between pallor and erythema.


MONDO:0008364

[PMID:29237099] [SUPPORT] Raynaud's phenomenon is a vasospastic disease characterized by digital pallor, cyanosis, and extremity pain. --- Explanation: Pain is a core characteristic feature of Raynaud phenomenon.


MONDO:0008364

[PMID:39040029] [SUPPORT] digital tissue damage frequently occurs in secondary RP but not primary RP --- Explanation: Digital ulceration is characteristic of secondary rather than primary RP.

[PMID:24418302] [SUPPORT] sRP can evolve and be complicated by acral digital ulcers and gangrene, which may require surgical treatment --- Explanation: Secondary RP can progress to digital ulcers and gangrene.


MONDO:0008364

[PMID:39040029] [SUPPORT] Pallor indicates reduced blood flow due to oxygen deprivation --- Explanation: Digital pallor reflects ischemia from vasospasm-induced blood flow reduction.


MONDO:0008364

[PMID:25770637] [INDIRECT EVIDENCE] [SUPPORT] alterations in activity of the peripheral adrenoceptor have been implicated, specifically an enhanced smooth muscle contraction due to overexpression or hyperactivity of postsynaptic alpha 2 receptors --- Explanation: Alpha-2 adrenoceptor hyperactivity drives the exaggerated smooth muscle contraction.

[PMID:40506673] [INDIRECT EVIDENCE] [SUPPORT] estrogen plays a fundamental role in potentiating the expression and function of α2C adrenoceptor (α2C-AR), the sole mediator of local cooling-induced vasoconstriction --- Explanation: Identifies alpha-2C-AR as the sole mediator of cold-induced vasospasm.


MONDO:0008364


MONDO:0008364

[PMID:39040029] [INDIRECT EVIDENCE] [SUPPORT] Raynaud's phenomenon (RP) is a condition characterized by episodic, excessive vasoconstriction in the fingers and toes, triggered by cold or stress. --- Explanation: Establishes the core vasospastic mechanism that RhoA/ROCK potentiates.


MONDO:0008364

[DOI:10.3390/ijms241814385] [INDIRECT EVIDENCE] [SUPPORT] Endothelial damage and activation occur early, possibly triggered by various infectious agents and autoantibodies. Endothelial dysfunction, along with defects in endothelial progenitor cells, leads to defective angiogenesis and vasculogenesis. --- Explanation: Endothelial dysfunction is an early event driving vascular pathology.

[DOI:10.3390/biomedicines12061331] [INDIRECT EVIDENCE] [SUPPORT] once damaged, endothelial cells can be dysfunctionally activated, thus becoming unable to undergo angiogenesis and promoting perivascular inflammation. They can also undergo apoptosis, transdifferentiate into profibrotic myofibroblasts --- Explanation: Describes mechanisms of endothelial dysfunction including EndoMT and failed angiogenesis in SSc-associated RP.


MONDO:0008364

[PMID:39040029] [INDIRECT EVIDENCE] [SUPPORT] The pathogenesis of RP involves a complex interaction between the vascular wall, nerves, hormones, and humoral factors, disrupting the balance between vasoconstriction and vasodilation. --- Explanation: Neurovascular dysregulation as a central mechanism.


MONDO:0008364

[DOI:10.1515/tjb-2023-0197] [INDIRECT EVIDENCE] [SUPPORT] A significant enrichment by gene ontology enrichment analysis was detected in a subset of genes involved in biological processes including cellular response to luteinizing hormone stimulus, negative regulation of fibrinolysis, negative regulation of smooth muscle cell apoptotic process, plasminogen activation --- Explanation: GO analysis of RP-associated genes shows enrichment in coagulation/fibrinolysis pathways relevant to intravascular abnormalities.

[DOI:10.1515/tjb-2023-0197] [INDIRECT EVIDENCE] [SUPPORT] Through the use of KEGG pathways, we were able to identify many molecular processes that contribute to RP, including the AGE-RAGE signaling pathway in diabetic complications, complement and coagulation cascades, fluid shear stress, atherosclerosis. --- Explanation: KEGG analysis confirms complement/coagulation cascade involvement in RP.


MONDO:0008364

[PMID:24418302] [INDIRECT EVIDENCE] [SUPPORT] recent advances in our understanding of the pathophysiology have highlighted novel potential therapeutic targets --- Explanation: Prete et al. review discusses pathogenic mechanisms including oxidative stress in RP pathophysiology.


MAXO:0000058

[PMID:39040029] [SUPPORT] Dihydropyridine calcium channel blockers (CCBs), such as nifedipine, are commonly used for vasodilation. --- Explanation: CCBs are established first-line pharmacotherapy for RP.

[PMID:29237099] [SUPPORT] CCBs (especially the dihydropyridine class) may be useful in reducing the frequency, duration, severity of attacks, pain and disability associated with Raynaud's phenomenon. --- Explanation: Cochrane systematic review of 38 RCTs demonstrating CCBs reduce attack frequency and severity.


CHEBI:7565

[PMID:39040029] [INDIRECT EVIDENCE] [SUPPORT] Dihydropyridine calcium channel blockers (CCBs), such as nifedipine, are commonly used for vasodilation. --- Explanation: CCBs are established first-line pharmacotherapy for RP.

[PMID:29237099] [INDIRECT EVIDENCE] [SUPPORT] CCBs (especially the dihydropyridine class) may be useful in reducing the frequency, duration, severity of attacks, pain and disability associated with Raynaud's phenomenon. --- Explanation: Cochrane systematic review of 38 RCTs demonstrating CCBs reduce attack frequency and severity.


CHEBI:2668


MAXO:0000950

[PMID:25770637] [SUPPORT] Most patients with RS can be managed conservatively, with avoidance of cold exposure or hand warming. --- Explanation: Conservative management with cold avoidance is first-line for most patients.


MAXO:0000058

[PMID:39040029] [SUPPORT] Phosphodiesterase-5 inhibitors and prostaglandin analogs are alternative options for patients who do not respond to CCBs or have ischemic tissue damage. --- Explanation: PDE5 inhibitors are second-line options for refractory RP.

[PMID:28281457] [SUPPORT] Sildenafil improved digital blood flow and RP symptoms in SSc patients after 8 weeks of treatment, and might be a good therapeutic option for secondary RP. --- Explanation: RCT demonstrating sildenafil improves microvascular blood flow in SSc-associated RP.


CHEBI:9139

[PMID:39040029] [INDIRECT EVIDENCE] [SUPPORT] Phosphodiesterase-5 inhibitors and prostaglandin analogs are alternative options for patients who do not respond to CCBs or have ischemic tissue damage. --- Explanation: PDE5 inhibitors are second-line options for refractory RP.

[PMID:28281457] [INDIRECT EVIDENCE] [SUPPORT] Sildenafil improved digital blood flow and RP symptoms in SSc patients after 8 weeks of treatment, and might be a good therapeutic option for secondary RP. --- Explanation: RCT demonstrating sildenafil improves microvascular blood flow in SSc-associated RP.


CHEBI:71940


MAXO:0000058

[PMID:39040029] [SUPPORT] Phosphodiesterase-5 inhibitors and prostaglandin analogs are alternative options for patients who do not respond to CCBs or have ischemic tissue damage. --- Explanation: Prostacyclin analogs are alternative options for severe/refractory RP.


CHEBI:63916

[PMID:39040029] [INDIRECT EVIDENCE] [SUPPORT] Phosphodiesterase-5 inhibitors and prostaglandin analogs are alternative options for patients who do not respond to CCBs or have ischemic tissue damage. --- Explanation: Prostacyclin analogs are alternative options for severe/refractory RP.


MAXO:0000058

[PMID:39040029] [SUPPORT] Bosentan, an endothelin-1 receptor antagonist, has shown effectiveness in treating and preventing digital ulcers, especially in patients with multiple ulcers. --- Explanation: Bosentan is effective for digital ulcer prevention in SSc-associated RP.


CHEBI:51450

[PMID:39040029] [INDIRECT EVIDENCE] [SUPPORT] Bosentan, an endothelin-1 receptor antagonist, has shown effectiveness in treating and preventing digital ulcers, especially in patients with multiple ulcers. --- Explanation: Bosentan is effective for digital ulcer prevention in SSc-associated RP.


MAXO:0000004

[PMID:39040029] [PARTIAL] sympathectomy surgery can be used to control RP symptoms. However, botulinum toxin injections require repeated administration, and sympathectomy's long-term effectiveness is uncertain. --- Explanation: Sympathectomy is an option for severe cases but has uncertain long-term efficacy.


ECTO:0001057

[PMID:40506673] [SUPPORT] Raynaud's phenomenon is a peripheral vascular disorder characterized by exaggerated vasoconstrictive response to certain stimuli, most typically cold exposure and emotional stress. --- Explanation: Cold exposure is the primary trigger for RP attacks.

[PMID:40506673] [SUPPORT] estrogen plays a fundamental role in potentiating the expression and function of α2C adrenoceptor (α2C-AR), the sole mediator of local cooling-induced vasoconstriction --- Explanation: Cold exposure activates alpha-2C-AR-mediated vasoconstriction.


MONDO:0400005

[PMID:19931071] [SUPPORT] Other metabolic abnormalities, such as hypokalemia and hypomagnesemia, may also occur, along with sodium and fluid retention. --- Explanation: Sodium and fluid retention during refeeding supports edema as a clinical manifestation.


MONDO:0400005

[PMID:19278172] [SUPPORT] Potential complications of RFS include fatal cardiac arrhythmia, systolic heart failure, respiratory insufficiency, and hematologic derangements. --- Explanation: This directly lists cardiac arrhythmia as a complication of refeeding syndrome.


MONDO:0400005

[PMID:19278172] [SUPPORT] Potential complications of RFS include fatal cardiac arrhythmia, systolic heart failure, respiratory insufficiency, and hematologic derangements. --- Explanation: This lists systolic heart failure as a complication of refeeding syndrome.


MONDO:0400005

[PMID:19278172] [SUPPORT] Potential complications of RFS include fatal cardiac arrhythmia, systolic heart failure, respiratory insufficiency, and hematologic derangements. --- Explanation: This directly lists respiratory insufficiency as a complication of refeeding syndrome.


MONDO:0400005

[PMID:41239620] [SUPPORT] Prolonged energy deficiency disrupts hematopoietic function, resulting in pancytopenia. --- Explanation: This case report notes pancytopenia in the context of severe malnutrition and refeeding syndrome.


MONDO:0400005

[PMID:41171118] [SUPPORT] RS itself becomes the cause of subsequent systemic complications such as respiratory failure, neurological disorders, circulatory failure or seizures. --- Explanation: This review lists seizures among systemic complications of refeeding syndrome.


MONDO:0400005

[PMID:38054139] [SUPPORT] received total parenteral nutrition (TPN) on the first day, but this led to delirium due to refeeding syndrome. --- Explanation: This case report describes delirium attributed to refeeding syndrome after initiating TPN.

[PMID:39033818] [SUPPORT] The incidence of delirium in critically ill patients is high and associated with refeeding hypophosphatemia. --- Explanation: This retrospective study reports high delirium incidence associated with refeeding hypophosphatemia, supporting a common frequency.


MAXO:0000009

[clinicaltrials:NCT02488109] [SUPPORT] The purpose of this study is to compare the efficacy, safety, and cost-effectiveness of lower calorie refeeding versus higher calorie refeeding in hospitalized adolescents with anorexia nervosa. --- Explanation: This trial evaluates caloric refeeding strategies, supporting controlled refeeding approaches.

[PMID:41171118] [SUPPORT] Current guidelines recommend a gradual increase in energy intake and regular monitoring of a patient's metabolic status (especially phosphorus, potassium, and magnesium levels) during nutritional treatment. --- Explanation: This review supports gradual energy advancement during refeeding.

[PMID:41239620] [SUPPORT] LESSONS: A stepwise calorie escalation protocol effectively corrects hypophosphatemia in refeeding syndrome. --- Explanation: This case report supports stepwise caloric escalation during refeeding.


MAXO:0000106

[PMID:41146174] [SUPPORT] Supplementation is indicated for severe or symptomatic cases, with oral therapy preferred for chronic conditions and intravenous routes for acute, severe hypophosphatemia. --- Explanation: This supports electrolyte supplementation as a management strategy for acute hypophosphatemia.

[PMID:41171118] [SUPPORT] Current guidelines recommend a gradual increase in energy intake and regular monitoring of a patient's metabolic status (especially phosphorus, potassium, and magnesium levels) during nutritional treatment. --- Explanation: This review supports monitoring phosphorus, potassium, and magnesium during refeeding.


MAXO:0010019

[PMID:29448987] [PARTIAL] thiamine deficiency and disorder of sodium and fluid balance are common. --- Explanation: Thiamine deficiency is common during refeeding, supporting prophylactic supplementation.


MAXO:0001262

[PMID:39947042] [SUPPORT] Benefits of early fasting responses have become clear, provided micronutrients are given to prevent deficiencies and refeeding syndrome. --- Explanation: This review supports providing micronutrients to prevent deficiencies and refeeding syndrome during nutrition management.


MONDO:0400005

[PMID:19931071] [SUPPORT] Refeeding syndrome (RFS) is the result of aggressive enteral or parenteral feeding in a malnourished patient, with hypophosphatemia being the hallmark of this phenomenon. --- Explanation: This identifies hypophosphatemia as the hallmark biochemical feature.


MONDO:0400005

[PMID:19278172] [SUPPORT] The typical patient who experiences RFS has been malnourished for days to weeks and develops hypophosphatemia and, occasionally, hypokalemia and hypomagnesemia when administered a carbohydrate load in the form of glucose-containing fluids, total parenteral nutrition (TPN), tube feedings, or an oral diet. --- Explanation: This describes hypokalemia as an occasional electrolyte abnormality during refeeding syndrome.


MONDO:0400005

[PMID:19278172] [SUPPORT] The typical patient who experiences RFS has been malnourished for days to weeks and develops hypophosphatemia and, occasionally, hypokalemia and hypomagnesemia when administered a carbohydrate load in the form of glucose-containing fluids, total parenteral nutrition (TPN), tube feedings, or an oral diet. --- Explanation: This identifies hypomagnesemia as an occasional electrolyte abnormality during refeeding syndrome.


MONDO:0005086

[PMID:6625621] [SUPPORT] Hematuria is an important symptom, and in our series 46% of the patients with renal cell carcinomas were conscious of macrohematuria as an initial symptom. --- Explanation: The abstract identifies hematuria as an important presenting symptom of RCC.


MONDO:0005086

[PMID:6625621] [SUPPORT] As an initial symptom, a mass was palpable in 8% and flank pain was felt in 13% of the patients with renal cell carcinomas. --- Explanation: The abstract reports flank pain as an initial symptom in RCC patients.


MAXO:0000004

[PMID:6625621] [SUPPORT] The most basic and reliable treatment method established for renal cell carcinomas is surgery--radical nephrectomy. --- Explanation: The abstract states radical nephrectomy is a basic and reliable treatment.


MAXO:0000058

[PMID:28898679] [SUPPORT] Unraveling the molecular biology and cytogenetic of RCC has enabled the development of several targeted agents that have improved treatment outcomes of these patients. --- Explanation: The abstract notes targeted agents as effective therapies for RCC.


MAXO:0000058

[PMID:39926260] [SUPPORT] Belzutifan received its first FDA approval in 2021 for treating clinical manifestations of von Hippel-Lindau (VHL) disease including renal cell carcinoma (RCC) followed by approval in 2023 for treating advanced sporadic RCC that has progressed through multiple lines of treatment. --- Explanation: The abstract describes belzutifan approvals for RCC treatment.


NCIT:C135627

[PMID:39926260] [INDIRECT EVIDENCE] [SUPPORT] Belzutifan received its first FDA approval in 2021 for treating clinical manifestations of von Hippel-Lindau (VHL) disease including renal cell carcinoma (RCC) followed by approval in 2023 for treating advanced sporadic RCC that has progressed through multiple lines of treatment. --- Explanation: The abstract describes belzutifan approvals for RCC treatment.


MONDO:0008380


MONDO:0008380

[PMID:5279523] [INDIRECT EVIDENCE] [PARTIAL] retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. --- Explanation: This is the foundational Knudson paper establishing the two-hit hypothesis based on statistical analysis of retinoblastoma cases.


MAXO:0000453


MAXO:0000647


CHEBI:31355


CHEBI:28445


CHEBI:4911


CHEBI:28876


MAXO:0000004


MAXO:0000014


HGNC.SYMBOL:RB1


MONDO:0008380

[PMID:41567907] [SUPPORT] Retinoblastoma is the most common intraocular malignancy in --- Explanation: Abstract notes retinoblastoma is the most common intraocular malignancy.


MONDO:0100099

[PMID:31236539] [SUPPORT] To propose and test the validity of a new syndrome called retrograde cricopharyngeus dysfunction (R-CPD) that explains inability to belch and the associated symptoms of loud gurgling noises, chest and abdominal pain/distention, and excessive flatulence --- Explanation: This landmark paper defined R-CPD and established inability to belch as the cardinal feature.

[PMID:37621856] [SUPPORT] A large constellation of hitherto unexplained symptoms including inability to burp, gurgling noises from the chest and lower neck, abdominal bloating, flatulence, painful hiccups and emetophobia was defined as Retrograde Cricopharyngeus Dysfunction (R-CPD) in 2019. --- Explanation: The Pavesi 2023 case report reiterates inability to burp as the defining symptom of R-CPD.

[PMID:38767031] [SUPPORT] The incapacity to belch is the hallmark of the disease. --- Explanation: The Jiménez-Castillo 2025 series states the hallmark symptom is inability to belch.

[PMID:36054518] [SUPPORT] The inability to burp (98.8%), bloating (92.9%), gurgling noises (31.8%), and excessive flatulence (21.2%) were the most common symptoms. --- Explanation: The Jefferson case series quantifies inability to burp as the dominant presenting symptom.

[PMID:38115814] [SUPPORT] 99% reported inability to burp, 98% reported abdominal bloating, 93% reported socially awkward gurgling noises, 89% reported excessive flatulence. --- Explanation: Survey data reinforce inability to burp as near-universal among affected patients.


MONDO:0100099

[PMID:35122356] [SUPPORT] The associated symptom complex includes some combination of chest pain, gurgling noises in the chest, bloating, nausea, hiccups, and flatulence. --- Explanation: Bloating (abdominal distention) is described as part of the core symptom complex of R-CPD.

[PMID:37621856] [SUPPORT] A large constellation of hitherto unexplained symptoms including inability to burp, gurgling noises from the chest and lower neck, abdominal bloating, flatulence, painful hiccups and emetophobia was defined as Retrograde Cricopharyngeus Dysfunction (R-CPD) in 2019. --- Explanation: The Pavesi 2023 case report lists abdominal bloating as a key symptom.

[PMID:38115814] [SUPPORT] 99% reported inability to burp, 98% reported abdominal bloating, 93% reported socially awkward gurgling noises, 89% reported excessive flatulence. --- Explanation: Community survey data show abdominal bloating affects nearly all respondents with R-CPD.


MONDO:0100099

[PMID:35122356] [SUPPORT] The associated symptom complex includes some combination of chest pain, gurgling noises in the chest, bloating, nausea, hiccups, and flatulence. --- Explanation: Chest pain is identified as a core symptom of retrograde UES dysfunction.


MONDO:0100099

[PMID:35122356] [SUPPORT] The associated symptom complex includes some combination of chest pain, gurgling noises in the chest, bloating, nausea, hiccups, and flatulence. --- Explanation: Nausea is described as part of the symptom complex associated with R-CPD.


MONDO:0100099

[PMID:31236539] [SUPPORT] To propose and test the validity of a new syndrome called retrograde cricopharyngeus dysfunction (R-CPD) that explains inability to belch and the associated symptoms of loud gurgling noises, chest and abdominal pain/distention, and excessive flatulence --- Explanation: Loud gurgling noises are described as a core feature of R-CPD.

[PMID:37621856] [SUPPORT] A large constellation of hitherto unexplained symptoms including inability to burp, gurgling noises from the chest and lower neck, abdominal bloating, flatulence, painful hiccups and emetophobia was defined as Retrograde Cricopharyngeus Dysfunction (R-CPD) in 2019. --- Explanation: Gurgling noises from the chest and lower neck are highlighted among the presenting symptoms.

[PMID:38115814] [SUPPORT] 99% reported inability to burp, 98% reported abdominal bloating, 93% reported socially awkward gurgling noises, 89% reported excessive flatulence. --- Explanation: Survey responses show gurgling noises are frequent in R-CPD.


MONDO:0100099

[PMID:35122356] [INDIRECT EVIDENCE] [SUPPORT] prior to 2019, there were only three case reports in the world literature of individuals with a physiologically demonstrated inability to belch due to failure of the UES to relax after gas venting from the stomach and ensuing low-pressure esophageal distention --- Explanation: The Kahrilas 2022 review establishes that UES relaxation failure during retrograde gas events is the core pathophysiological mechanism.

[PMID:38587015] [INDIRECT EVIDENCE] [SUPPORT] RCPD is associated with a longer UES, elevated UES basal pressures, and an increased incidence of ineffective esophageal motility. --- Explanation: The Yousef 2024 case-control study demonstrated physiological abnormalities in UES function in R-CPD patients.

[PMID:41506952] [INDIRECT EVIDENCE] [SUPPORT] high-resolution manometry was performed on both patients, showing elevated basal upper esophageal sphincter (UES) pressure and absence of UES relaxation with attempted belching. --- Explanation: The Dealino 2026 cases document absent UES relaxation during attempted belching.

[PMID:38767031] [INDIRECT EVIDENCE] [SUPPORT] We performed HRM with a belch provocation test for which the patient drank 500 ml of carbonated water. The study revealed increased esophageal pressure, an absence of UES relaxation and secondary peristalsis once the patient mentioned the need to belch. --- Explanation: The Jiménez-Castillo 2025 case series shows failure of UES relaxation during retrograde distension.


MONDO:0100099


MONDO:0100099

[PMID:38587015] [INDIRECT EVIDENCE] [SUPPORT] The RCPD cohort, compared to the asymptomatic cohort, exhibited significantly greater upper esophageal sphincter (UES) length [4.5 (SD: 0.7) vs 3.7 (0.9) cm --- Explanation: The case-control study quantified higher UES basal pressures in R-CPD patients relative to controls.

[PMID:41506952] [INDIRECT EVIDENCE] [SUPPORT] high-resolution manometry was performed on both patients, showing elevated basal upper esophageal sphincter (UES) pressure and absence of UES relaxation with attempted belching. --- Explanation: Elevated resting UES pressure was observed in both cases in the 2026 report.


MAXO:0009016

[PMID:31236539] [SUPPORT] All 51 patients achieved ability to belch and relief of associated symptoms, and the majority seem to have "retrained" the ability to belch on a potentially "permanent" basis. --- Explanation: The Bastian 2019 case series demonstrated 100% success rate with botulinum toxin injection in restoring belching ability.

[PMID:38587015] [SUPPORT] All patients who underwent cricopharyngeal botulinum injections experienced initial improvement of symptoms with 3 patients requiring repeat intervention. --- Explanation: The Yousef 2024 study confirms botulinum toxin as an effective treatment.

[PMID:37621856] [SUPPORT] successfully treated with unilateral, anesthesia-free injection of 10 units of onabotulinum toxin into the cricopharyngeus muscle, representing the lowest dose reported to date. --- Explanation: The Pavesi 2023 case report demonstrates symptom resolution with low-dose botulinum toxin.

[PMID:41200864] [SUPPORT] This transtracheal technique for cricopharyngeal botulinum toxin injection is a safe and effective option for chemodenervation of this muscle in the awake patient. --- Explanation: The Tritter 2025 procedural report supports safety and effectiveness of the transtracheal botulinum approach.

[PMID:41506952] [SUPPORT] previously undergone percutaneous botulinum toxin injection that initially provided temporary relief. --- Explanation: The Dealino 2026 case notes symptomatic improvement after botulinum toxin injection.

[PMID:40411338] [SUPPORT] The immediate success rate of botulinum toxin injection into the cricopharyngeal sphincter in facilitating burping was 92.5%. --- Explanation: Systematic review reports high immediate success for botulinum toxin in R-CPD.

[PMID:39883449] [SUPPORT] The cumulative success rate of BTI was 90.6% (96 of 106 patients). --- Explanation: In-office botulinum injections achieved high cumulative success in a 106-patient series.

[PMID:38576368] [SUPPORT] At median follow-up of 29 months (range, 3-50) post-treatment, 51.3% (n = 20/39) of patients reported persistent complete relief of symptoms --- Explanation: Belgian case series quantifies short- and long-term response rates to botulinum toxin.


MONDO:0010726

[PMID:10508514] [PARTIAL] Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use --- Explanation: Original discovery paper documents developmental regression with loss of speech and hand skills as hallmark of Rett syndrome.


MONDO:0010726

[PMID:10508514] [PARTIAL] develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements --- Explanation: Original discovery paper identifies stereotypic hand movements as core feature of Rett syndrome.


MONDO:0010726

[PMID:10508514] [PARTIAL] develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements --- Explanation: Original discovery paper lists ataxia as a cardinal feature of Rett syndrome.


MONDO:0010726

[PMID:10508514] [PARTIAL] develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements --- Explanation: Original discovery paper lists microcephaly as a cardinal feature of Rett syndrome.


MONDO:0010726

[PMID:10508514] [PARTIAL] develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements --- Explanation: Original discovery paper lists seizures as a cardinal feature of Rett syndrome.


MONDO:0010726

[PMID:23103540] [SUPPORT] hyperventilation and apnea during wakefulness were present in all patients --- Explanation: Study confirms breathing abnormalities including hyperventilation and apnea are universal in Rett syndrome patients.


MONDO:0010726


MONDO:0010726

[PMID:10508514] [INDIRECT EVIDENCE] [PARTIAL] MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A --- Explanation: Original discovery paper confirms MeCP2 functions as a transcriptional regulator through DNA methylation binding.


MONDO:0010726

[PMID:24615633] [INDIRECT EVIDENCE] [PARTIAL] Rett syndrome (RTT) is a severe and progressive neurological disorder, which mainly affects young females. Mutations of the methyl-CpG binding protein 2 (MECP2) gene are the most prevalent cause of classical RTT cases. --- Explanation: Review confirms MECP2 mutations cause the neurological dysfunction in Rett syndrome.


HGNC.SYMBOL:MECP2

[PMID:10508514] [SUPPORT] we have identified mutations in the gene (MECP2) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT --- Explanation: Original discovery paper identified MECP2 mutations as the cause of Rett syndrome.


MONDO:0008383

[PMID:29848426] [PARTIAL] More than 50% patients with JIA have joint deformities. Joint deformities are more likely to be seen in children with long-standing disease, those with polyarthritis JIA and seropositive patients. --- Explanation: This supports the association between polyarthritis and joint deformity, but it is specific to Juvenile Idiopathic Arthritis (JIA) and does not fully address symmetric polyarthritis in RA.

[PMID:37410796] [SUPPORT] Incident RA presents mainly as symmetric arthritis. --- Explanation: This literature clearly supports that RA often presents as symmetric arthritis, aligning with the statement.

[PMID:37158761] [SUPPORT] Symmetrical involvement of the hand joints is described as characteristic of rheumatoid arthritis (RA). --- Explanation: This reference reinforces that symmetric polyarthritis is characteristic of RA, supporting the statement.

[PMID:22035393] [PARTIAL] Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder affecting multiple organ systems, joints, ligaments, and bones and commonly involves the cervical spine. --- Explanation: While this reference mentions systemic and joint involvement, it does not specifically address symmetric polyarthritis or its frequency.

[PMID:11358413] [NO_EVIDENCE] RA is now thought to be associated with a conserved sequence of amino acids in a number of HLA-DRB1 alleles, called the RA shared epitope --- Explanation: This suggests a genetic predisposition to more severe and chronic forms of RA, which could include symmetric polyarthritis, thus supporting the statement.


MONDO:0008383

[PMID:26403254] [PARTIAL] These recommendations serve to guide rheumatologists and other stakeholders on the assessment and management of morning stiffness. --- Explanation: The literature states that morning stiffness is a significant symptom in rheumatoid arthritis (RA) and is commonly associated with functional disability and pain. This supports the statement that morning stiffness is a common phenotype in RA.

[PMID:36544060] [SUPPORT] Rheumatoid arthritis symptoms follow a 24 h circadian rhythm and exhibit high thresholds of pain, functional disability, and stiffness predominantly early in the morning. --- Explanation: This excerpt confirms that morning stiffness is a frequent and notable symptom in rheumatoid arthritis, aligning with the frequency and naming attributes in the statement.

[PMID:24461540] [NO_EVIDENCE] The typical symptoms are bilateral aching of the shoulder girdle, associated with morning stiffness. --- Explanation: The reference notes that morning stiffness is a symptom associated with polymyalgia rheumatica and also mentions its relevance in diagnosing inflammatory rheumatic diseases, which includes RA.


MONDO:0008383

[PMID:25005390] [SUPPORT] Many of these people experience pain, inflammation, stiffness, reduced mobility and joint function, and fatigue. --- Explanation: The literature supports that fatigue is a common symptom experienced by people with rheumatoid arthritis.

[PMID:26803313] [NO_EVIDENCE] Fatigue occurs in all chronic inflammatory diseases, in cancer, and in some neurological conditions. --- Explanation: This supports the notion that fatigue is a common systemic phenotype in rheumatoid arthritis.

[PMID:38643104] [PARTIAL] Patients with RA reported worse outcomes for all PROMs than those with CSA or UA. --- Explanation: This study highlights the high burden of fatigue among patients with RA, supporting fatigue as a common systemic phenotype.


MONDO:0008383

[PMID:20559644] [SUPPORT] The main spectrum of eye involvement comprises keratoconjunctivitis sicca, episcleritis and scleritis as well as ulcerative keratitis. --- Explanation: This reference indicates that scleritis is part of the spectrum of eye involvement in rheumatoid arthritis, supporting the statement.

[PMID:37344292] [SUPPORT] Rheumatoid arthritis and systemic vasculitides, particularly antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides, are the main autoimmune causes of scleritis and episcleritis. --- Explanation: This reference supports that scleritis is associated with rheumatoid arthritis.

[PMID:30412434] [SUPPORT] Rheumatoid arthritis and Wegener granulomatosis were the 2 most common systemic associations among our cohort. --- Explanation: This reference confirms that rheumatoid arthritis is a common systemic association with scleritis.

[PMID:10879785] [SUPPORT] Ocular manifestations commonly include episcleritis, scleritis, conjunctivitis, iridocyclitis, chorioretinitis, and proptosis. --- Explanation: This reference supports the association between rheumatoid arthritis and scleritis.


MONDO:0008383

[PMID:33216192] [PARTIAL] Pericarditis is the term for inflammatory involvement of the pericardium, which can be associated with pericardial effusion and myocardial involvement (perimyocarditis). Pericarditis can be present in the context of systemic inflammatory rheumatic diseases but can also constitute a distinct disease entity. --- Explanation: This reference confirms that pericarditis can be present in systemic inflammatory rheumatic diseases, including rheumatoid arthritis, indicating it can occur as a cardiovascular manifestation.

[PMID:11055006] [SUPPORT] Pericardial effusion is common in patients with rheumatoid arthritis. It is essentially a sign of pericardial involvement of the rheumatoid disease. --- Explanation: This reference directly states that pericardial effusion, which is indicative of pericarditis, is common in rheumatoid arthritis patients, supporting the statement.


MONDO:0008383


MONDO:0008383

[PMID:22608255] [INDIRECT EVIDENCE] [SUPPORT] Rheumatoid arthritis (RA) is an autoimmune disease, characterized by chronic inflammation and synovial hyperplasia in the joints that ultimately lead to cartilage and bone destruction. A wealth of research has shown that CD4(+) T cells, especially IL-17 producing helper T (Th17) cells, play an important role in RA development. --- Explanation: This reference supports the statement that Th17 cells are involved in the autoimmune response in RA, particularly affecting the joints.

[PMID:30572135] [INDIRECT EVIDENCE] [SUPPORT] These pro-inflammatory T-cells are also key players in autoimmunity and a pathogenic role has been demonstrated in several diseases such as rheumatoid arthritis or psoriasis. --- Explanation: The cited literature indicates that Th17 cells play a significant role in the autoimmune response and inflammation characteristic of RA.

[PMID:31895885] [INDIRECT EVIDENCE] [SUPPORT] Rheumatoid arthritis (RA) is a prototypic autoimmune disease manifesting as chronic inflammation of the synovium and leading to acceleration of cardiovascular disease and shortening of life expectancy. --- Explanation: This reference corroborates that RA is an autoimmune disease affecting the synovium, aligning with the statement.


MONDO:0008383

[PMID:9836373] [INDIRECT EVIDENCE] [PARTIAL] Rheumatoid arthritis (RA) is well known to be a chronic autoimmune/inflammatory disease which leads to progressive joint damage and destruction. --- Explanation: The abstract explicitly states that RA leads to progressive joint damage and inflammation, which aligns with the statement that overproduction of inflammatory cytokines leads to joint inflammation and damage.

[PMID:34688020] [INDIRECT EVIDENCE] [SUPPORT] This pleiotropic cytokine [IL-6] is a key factor in the pathogenesis of rheumatoid arthritis (RA) and is involved in many extra-articular manifestations that accompany the disease. --- Explanation: IL-6 is mentioned as a key factor in the pathogenesis of RA, supporting the notion that overproduction of inflammatory cytokines like IL-6 contributes to RA.

[PMID:32830085] [INDIRECT EVIDENCE] [PARTIAL] The pro-inflammatory mediators released via interaction of intracellular kinases direct the development of Rheumatoid arthritis. --- Explanation: The abstract clearly states that pro-inflammatory mediators direct the development of RA, which supports the statement about the role of cytokines like TNF-α, IL-1, and IL-6 in joint inflammation and damage.

[PMID:33692806] [INDIRECT EVIDENCE] [PARTIAL] IL-23/IL-17 axis activation contributes to the development of several inflammatory diseases, such as ... Rheumatoid Arthritis. --- Explanation: Although focusing on IL-23/IL-17, the review also discusses other inflammatory cytokines such as IL-6 and TNF-α and their role in RA, which supports the statement.


MONDO:0008383

[PMID:15353290] [INDIRECT EVIDENCE] [SUPPORT] Rheumatoid arthritis (RA) is a chronic inflammatory disease with progressive articular damage. Activated cells of the synovium produce pro-inflammatory and matrix-degrading effector molecules, which maintain the inflammation and lead to the destruction of the involved joints. In addition to macrophages and T- and B-cells, fibroblast-like synoviocytes must be considered key cells in driving the pathological processes. They can be distinguished by their transformed-appearing phenotype and their invasion into adjacent cartilage and bone. --- Explanation: The literature describes that fibroblast-like synoviocytes and macrophages play a key role in the inflammation and invasion of cartilage and bone in RA, supporting the statement.

[PMID:35958604] [INDIRECT EVIDENCE] [PARTIAL] Synovial hyperplasia often presents when joints become inflamed due to immune cell infiltration. Synovial membrane... interact with synovial fibroblasts (SFs), T cells, B cells, and other inflammatory cells to promote the production of a variety of pro-inflammatory cytokines and chemokines, such as TNF-alpha, IL-1beta, IL-8, and IL-6, which are involved in the pathogenic process of inflammatory arthritis. --- Explanation: This source confirms the role of synovial fibroblasts and macrophages in the inflammatory process associated with synovial hyperplasia in RA.

[PMID:29287304] [INDIRECT EVIDENCE] [SUPPORT] Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by destructive hyperplasia of the synovium. Fibroblast-like synoviocytes (FLS) are a major component of synovial pannus and actively participate in the pathologic progression of RA. --- Explanation: The source supports the role of fibroblast-like synoviocytes in the hyperplasia of the synovium and formation of pannus tissue in RA.


MONDO:0008383

[PMID:28597065] [INDIRECT EVIDENCE] [SUPPORT] Structural damage of cartilage and bone tissue is a hallmark of rheumatoid arthritis (RA). The resulting joint destruction constitutes one of the major disease consequences for patients... These factors result in an inflammatory milieu in the affected joints which leads to an increased development and function of osteoclasts.

[PMID:17634141] [INDIRECT EVIDENCE] [PARTIAL] Chronic inflammatory arthritis not only leads to inflammatory bone loss but it also involves local erosion of articular bone. This osteo-destructive feature of chronic inflammatory arthritis is a major cause of disability in patients with rheumatoid arthritis.

[PMID:24217093] [INDIRECT EVIDENCE] [SUPPORT] Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by joint swelling, joint tenderness and destruction of synovial joints, leading to severe disability.

[PMID:35273387] [INDIRECT EVIDENCE] [SUPPORT] Rheumatoid arthritis can involve localized, periarticular bone erosion...The RANK-RANKL-osteoprotegerin axis and the Wnt-beta-catenin signalling pathway...have been implicated in inflammatory bone loss.


MONDO:0008383

[PMID:35367240] [INDIRECT EVIDENCE] [SUPPORT] the JAK-STAT pathway has been majorly implicated in RA disease progression upon IL-6 stimulation --- Explanation: This review demonstrates that JAK-STAT signaling is central to IL-6 mediated pathogenesis in rheumatoid arthritis, and that JAK inhibitors are clinically effective in treating RA by abrogating this signaling pathway.


MAXO:0000058

[PMID:11899747] [NO_EVIDENCE] NSAID toxicity mostly affected the GI tract. There was a similar incidence of GI-related adverse events between patients with and patients without GI protection, mainly dyspepsia and nausea. NSAIDs have the potential to cause adverse events in the GI tract. --- Explanation: The provided literature indicates that NSAIDs are used in the treatment of rheumatoid arthritis (RA) and can help alleviate pain, despite some potential side effects, thus supporting the statement.

[PMID:29100265] [NO_EVIDENCE] This review will give a concise summary on the available studies on the application of nano-formulated drugs designed for pain treatment and management. --- Explanation: This reference mentions the effectiveness of NSAIDs in pain management, supporting the statement.

[PMID:23083758] [NO_EVIDENCE] NSAIDs reduce pain and stiffness effectively in most patients, are able to reduce systemic and local inflammation, and can inhibit progression of structural damage in the spine. --- Explanation: This indicates that NSAIDs are effective in reducing pain and inflammation in conditions similar to RA, thus supporting the statement.

[PMID:27278642] [NO_EVIDENCE] By examining confounds and limitations in the available literature it is suggested that current data suggest that only a sub-group of individuals with major depressive disorder (MDD) have evidence of increased inflammatory biomarkers and it is in these individuals that anti-inflammatory agents show promise for reducing depressive symptoms. --- Explanation: While the reference primarily discusses the use of NSAIDs for major depressive disorder, it hints at the effectiveness of NSAIDs in reducing inflammation, partially supporting the statement.


MAXO:0000058

[PMID:14969069] [SUPPORT] Disease-modifying anti-rheumatic drugs (DMARDs) used in combination appear to be more effective than monotherapies at reducing the rate of progressive joint damage during randomized controlled trials. --- Explanation: This statement directly supports the idea that DMARDs slow disease progression and prevent joint damage.

[PMID:8601050] [SUPPORT] Methotrexate is presently the most popular of the DMARDs for the treatment of rheumatoid arthritis. Methotrexate inhibits dihydrofolate reductase and adenosine release and has a secondary effect on cytokines and polymorphonuclear chemotaxis. It is highly metabolised within cells and remains there for prolonged periods. --- Explanation: This excerpt indicates methotrexate's mechanisms in treating RA, affirming its role in slowing disease progression and preventing joint damage.

[PMID:25172238] [SUPPORT] According to the results of several head-to-head comparative trials against other synthetic DMARDs, MTX has been recognised as the 'anchor drug' for the treatment of RA. --- Explanation: This confirms methotrexate's effectiveness as a primary treatment in managing RA, thus supporting the statement.

[PMID:35953230] [SUPPORT] Key recommendations are to start effective treatment immediately with DMARDs to reduce disability; use effective doses of methotrexate (oral or subcutaneous) with folic acid as the initial treatment; rapidly escalate treatment with various DMARDs, if methotrexate alone is not effective in controlling rheumatoid arthritis. --- Explanation: This supports the statement by advising DMARDs to prevent disease progression and joint damage.


MAXO:0000058

[PMID:22166850] [SUPPORT] Rheumatoid arthritis (RA) remains a major clinical problem, but treatments involving biologics have revolutionized its management. They target pathogenically relevant cytokines such as tumor necrosis factor and immune cells such as B cells. --- Explanation: This reference confirms that biologics used in the treatment of RA target specific components of the immune system, including cytokines like TNF-α.

[PMID:25697599] [SUPPORT] Anticytokine therapy for inflammatory diseases became a clinical reality with the introduction of tumor necrosis factor (TNF) inhibitors for the treatment of severe rheumatoid arthritis. --- Explanation: The reference highlights that anticytokine therapies, including TNF inhibitors, are used in RA treatment, thus supporting the statement.

[PMID:32550671] [SUPPORT] Cytokine blockers were the first to be developed and rapidly expanded. They include agents that act against tumor necrosis factor alpha (TNF-α)... and interleukin (IL) 6 (tocilizumab and sarilumab). --- Explanation: The reference supports that biologics used for RA treatment include TNF-α inhibitors and IL-6 inhibitors, which target specific components of the immune system.


MAXO:0000058

[PMID:28043173] [PARTIAL] Glucocorticoids - be it conventional or modified/delayed-release formulations - have so far been convincing in clinical practice, and their widespread use will therefore continue. --- Explanation: The literature supports the use of glucocorticoids for the treatment of rheumatoid arthritis, highlighting their efficacy. However, it does not specify that they are used for short-term control of flares or as bridge therapy, thus only partially supporting the precise conditions mentioned in the statement.

[PMID:24527481] [PARTIAL] The family physician plays several important roles in the management of patients with RA by early diagnosis of RA, with initiation of synthetic DMARD therapy, and in long-term follow-up to minimize complications of DMARD therapy and its impact on patient comorbidities. --- Explanation: This reference mentions the management and use of various therapies for rheumatoid arthritis, but it does not explicitly discuss the short-term use or glucocorticoids as bridge therapy, providing only partial support.

[PMID:29745893] [PARTIAL] Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids and disease-modifying antirheumatic drugs (DMARDs) are widely used to treat RA patients. --- Explanation: This literature confirms the use of corticosteroids (which include glucocorticoids) in treating RA but does not specify their role as short-term or bridge therapy, thereby partially supporting the statement.


MAXO:0000011

[PMID:15266230] [SUPPORT] Physiotherapy and rehabilitation applications significantly augment medical therapy by improving the management of RA and reducing handicaps in daily living for patients with RA. --- Explanation: The literature supports the effectiveness of physiotherapy in managing RA, including maintaining joint mobility and reducing disabilities.

[PMID:25748549] [SUPPORT] The exercise programme consisted of six sessions of strengthening and stretching exercises with a hand therapist, daily home exercises and strategies to maximise adherence. --- Explanation: The results indicate that exercise programmes included in physical therapy can be effective in maintaining joint function and strengthening muscles in RA patients.

[PMID:9667624] [SUPPORT] The results suggest that dynamic exercise therapy is effective in increasing aerobic capacity and muscle strength. --- Explanation: Dynamic exercise therapy, a component of physical therapy, has been shown to improve muscle strength and maintain physical capacity in RA patients.


HGNC.SYMBOL:HLA-DRB1

[PMID:24447879] [SUPPORT] HLA-DRB1*04 was found to have increased frequency in the RA group compared to controls (P < 0.001, OR = 3.14)...HLA-DRB1*04:05 was associated with RA (P = 0.005, OR = 3.41) --- Explanation: The study shows an increased frequency of HLA-DRB1*04 and HLA-DRB1*04:05 in the RA group, indicating an association with increased risk.

[PMID:32638005] [SUPPORT] This review identifies the most significant genetic variants associated with RA susceptibility to date, with particular focus on the contribution of the HLA class II genes across different ethnic groups. --- Explanation: The review discusses the significant role of HLA-DRB1 in RA susceptibility.

[PMID:16542468] [SUPPORT] HLA-DR alleles such as HLA-DR4 and HLA-DR1 are associated with the risk to develop RA. --- Explanation: HLA-DR4, a subtype of HLA-DRB1, is associated with an increased risk of developing RA.

[PMID:32370106] [SUPPORT] Association studies of the HLA-DRB1 gene clearly indicate its importance in RA morbidity. --- Explanation: The review presents the current understanding of HLA-DRB1's role in increasing the risk of RA.

[PMID:24336335] [SUPPORT] Certain HLA-DRB1 alleles and single-nucleotide polymorphisms (SNPs) are associated with rheumatoid arthritis (RA). --- Explanation: The study reinforces the association of HLA-DRB1 alleles with RA.

[PMID:3067866] [SUPPORT] Part of this genetic predisposition is accounted for by genes within the MHC where there is a well-documented association with HLA-DR4. --- Explanation: The study mentions the association of HLA-DR4, a subtype of HLA-DRB1, with RA.

[PMID:29037901] [NO_EVIDENCE] HLA-DRB1*01 and HLA-DRB1*04 may be involved in the genetic predisposition of Rheumatoid Factor (RF) positive forms of JIA. --- Explanation: The meta-analysis highlights the role of HLA-DRB1 alleles in RA-related conditions, such as juvenile idiopathic arthritis.

[PMID:36155967] [PARTIAL] We evaluated whether RA-ILD is associated with these genetic variants and HLA-DRB1 shared epitope (SE) alleles in a large RA cohort stratified by race and smoking history. --- Explanation: The study discusses the association of HLA-DRB1 SE alleles with RA-ILD.


HGNC.SYMBOL:PTPN22

[PMID:30957405] [SUPPORT] The overall effect of PTPN22-1123 on RA risk in all genetic random models showed significant positive associations. --- Explanation: The study found significant positive associations between PTPN22 genetic variations and increased risk of rheumatoid arthritis.

[PMID:15790351] [SUPPORT] A functional variant (R620W) of the intracellular protein tyrosine phosphatase N22 (PTPN22) has now been conclusively shown to confer approximately two-fold risk for seropositive RA as well as several other autoimmune disorders. --- Explanation: The variant R620W of PTPN22 is associated with a significantly increased risk of rheumatoid arthritis.

[PMID:15838240] [SUPPORT] The second risk factor for rheumatoid arthritis, the PTPN22 polymorphism, has been identified. --- Explanation: The PTPN22 polymorphism has been identified as a genetic risk factor for rheumatoid arthritis.


HGNC.SYMBOL:STAT4

[PMID:30864557] [SUPPORT] Herein, we found a significant positive association between minor T allele as well as different genotypes with the risk of RA. --- Explanation: The study found a significant positive association between the STAT4 gene rs7574865 SNP and the risk of rheumatoid arthritis (RA).

[PMID:20453440] [SUPPORT] We and other investigators also found that IRF5, STAT4 and BLK are associated not only with SLE, but also rheumatoid arthritis and systemic sclerosis. --- Explanation: The literature supports an association between the STAT4 gene and increased risk of rheumatoid arthritis.


HGNC.SYMBOL:CTLA4

[PMID:34339393] [SUPPORT] This meta-analysis confirmed that rs3087243 and rs231775 polymorphism were associated with the risk of RA in both overall population and ethnic-specific analysis, but there was no association between rs5742909 polymorphism and RA risk --- Explanation: The meta-analysis provides evidence that CTLA-4 gene polymorphisms are associated with an increased risk of rheumatoid arthritis.

[PMID:35758965] [SUPPORT] There was a significantly higher median (inter-quartile range) expression of CTLA-4 and CCL2 in RA patients in comparison to controls (P < 0.05) --- Explanation: The study found significantly higher expression of CTLA-4 in RA patients, supporting the association of CTLA-4 with increased RA risk.

[PMID:11196709] [SUPPORT] For most autoimmune disorders... the gene encoding cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been suggested as a candidate gene for conferring susceptibility to autoimmunity. --- Explanation: The article discusses CTLA4 as a candidate gene for susceptibility to autoimmune diseases, including rheumatoid arthritis.


HGNC.SYMBOL:PADI4

[PMID:17893996] [SUPPORT] peptidylarginine deiminase (gene name abbreviated to PADI, protein name abbreviated to PAD) type 4 is the one of the non-HLA genetic factors involved in RA via citrullination --- Explanation: This review identifies PADI4 as a key non-HLA genetic susceptibility factor for RA, demonstrating the link between citrullination of proteins and generation of autoantigens targeted by anti-citrullinated protein antibodies.


HGNC.SYMBOL:PADI2


HGNC.SYMBOL:TNF


HGNC.SYMBOL:IL6R


HGNC.SYMBOL:TYK2


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:REL


HGNC.SYMBOL:PRDM1


HGNC.SYMBOL:IL21R


ECTO:6000029

[PMID:22609003] [SUPPORT] Smoking is associated with an increased risk of developing seropositive RA (RF and/or ACPA). Recent studies show that tobacco smoking can influence disease phenotype, with the development of more aggressive disease and greater joint damage. --- Explanation: The literature indicates that smoking increases the risk of developing seropositive RA and may lead to more severe disease outcomes, which aligns with the statement.

[PMID:12860726] [SUPPORT] In a multivariate analysis the main predictors of severe ExRA were smoking at RA diagnosis (risk ratio (RR)=2.94; 95% confidence interval (95% CI) 1.68 to 5.13). --- Explanation: This reference indicates smoking as a significant predictor of severe extra-articular manifestations in RA, supporting the statement about severity.

[PMID:36155967] [SUPPORT] MUC5B and TOLLIP single nucleotide polymorphisms (SNPs) and cigarette smoking were associated with rheumatoid arthritis-interstitial lung disease (RA-ILD). --- Explanation: Smoking is listed as a risk factor for RA and its associated complications, such as interstitial lung disease.


ECTO:3000000

[PMID:28516867] [PARTIAL] Extensive data supports the roles of genetic, environmental and microbial factors in the triggering and development of this disease. Proteus mirabilis is considered as the main microbial culprit in the causation of RA. --- Explanation: This reference supports the role of infections, specifically microbial factors, as potential environmental triggers for the onset of rheumatoid arthritis.

[PMID:32582191] [PARTIAL] In conclusion, we retrieved more than one line of evidence for mucosal sites and different microbial taxa to be potentially involved in the development of RA. --- Explanation: This reference provides multiple lines of evidence suggesting that infections, specifically from various microbial taxa, are potential contributors to the onset of rheumatoid arthritis.

[PMID:35897715] [PARTIAL] Possible mechanisms involving environmental and individual factors in RA pathogenesis were analyzed, namely, infections, mental stress, sleep deprivation ecology, age, perinatal and gender factors, eating habits, obesity and smoking. --- Explanation: This reference explicitly includes infections among the environmental factors that may contribute to the onset of RA.


MONDO:0014722

[PMID:35450878] [PARTIAL] Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency. We wish to add to the available literature by reporting two brothers with clinical, radiological and immunological features of Roifman syndrome, confirmed on whole exome sequencing. --- Explanation: The reference confirms that Roifman syndrome is an immunologic disorder and mentions immunodeficiency, but it does not provide explicit details about the frequency or severity of recurrent infections.

[PMID:33059947] [PARTIAL] Roifman syndrome is an allelic disorder of MOPD I that is characterized by immunodeficiency complications. --- Explanation: The reference describes Roifman syndrome as having immunodeficiency complications, but does not specifically mention the frequency or severity of recurrent infections.


MONDO:0014722

[PMID:35450878] [PARTIAL] Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency... New radiological features are also described here which may assist in the diagnosis of other patients. --- Explanation: The reference mentions new radiological features but does not explicitly confirm that growth retardation and skeletal abnormalities are very frequent in Roifman syndrome.

[PMID:29265708] [PARTIAL] RNU4ATAC pathogenic variants to date have been associated with microcephalic osteodysplastic primordial dwarfism, type 1 and Roifman syndrome. Both conditions are clinically distinct skeletal dysplasias... Some of the overlapping features of the two conditions include developmental delay, microcephaly, and immune deficiency. --- Explanation: The reference mentions Roifman syndrome as a skeletal dysplasia with developmental delay and microcephaly, but does not explicitly confirm short stature and skeletal abnormalities as very frequent.


MONDO:0014722

[PMID:21910238] [SUPPORT] The results confirmed a stable pattern of intellectual disability, and indicated that Roifman syndrome may be associated with major structural neuro-anatomical abnormalities. --- Explanation: The literature confirms that intellectual disability is a feature of Roifman syndrome.


MONDO:0014722

[PMID:8172269] [NO_EVIDENCE] We studied 573 patients with the Marfan syndrome for the presence of ocular misalignment, refractive errors, and amblyopia. A total of 110 patients (19.2%) had strabismus. --- Explanation: The study focuses on the prevalence of strabismus in Marfan syndrome, not Roifman syndrome.

[PMID:4988135] [NO_EVIDENCE] Heredity and strabismus. --- Explanation: The reference discusses the hereditary nature of strabismus but does not mention Roifman syndrome.


MONDO:0014722

[PMID:35063500] [INDIRECT EVIDENCE] [SUPPORT] We sought to determine whether disease-associated mutations in TOP2B impact NK-cell development and function. ... Mature NK cells were reduced in the periphery of TOP2B knockin mice consistent with patient reports, with reduced cytotoxicity toward target cell lines. --- Explanation: The study indicates that mutations associated with Hoffman syndrome, which is another syndromic immunodeficiency, result in decreased NK cell function. This supports the statement about Roifman syndrome having decreased NK cell function due to the similarity in the impact on NK cells.


MONDO:0014722

[PMID:29391254] [INDIRECT EVIDENCE] [PARTIAL] The patients exhibited a dramatic reduction in B-cell numbers, with differentiation halted at the transitional B-cell stage. --- Explanation: The study confirms a dramatic reduction in total B-cell numbers in Roifman syndrome patients but does not specifically mention memory B cells.


MAXO:0000058

[PMID:26454315] [PARTIAL] Immunoglobulin replacement therapy has been standard treatment in patients with primary immunodeficiency diseases for the past 3 decades. The goal of therapy is to reduce serious bacterial infections in individuals with antibody function defects. --- Explanation: While the literature supports that immunoglobulin replacement therapy is used to reduce serious bacterial infections in primary immunodeficiency diseases, it does not specifically mention Roifman syndrome. Therefore, the support is partial.

[PMID:21977988] [NO_EVIDENCE] Roifman syndrome is a rare syndrome of bone dysplasia, growth retardation, retinal dystrophy and humeral immunodeficiency. --- Explanation: The literature describes Roifman syndrome and its characteristics but does not provide evidence regarding the use of immunoglobulin replacement therapy for preventing infections in this syndrome.


MAXO:0000058

[PMID:35450878] [NO_EVIDENCE] We report an excellent response to subcutaneous immunoglobulin therapy in both brothers, reducing infection burden and hospital admissions. --- Explanation: The literature mentions the use of subcutaneous immunoglobulin therapy to reduce infection burden in Roifman syndrome but does not provide evidence for the use of antibiotic prophylaxis.


MAXO:0000283

[PMID:10905663] [NO_EVIDENCE] This report describes a fifth individual with co-existent hypogonadotrophic hypogonadism, thereby expanding the phenotype and possibly offering insight into the genetic aetiology of this condition. --- Explanation: The reference describes the characteristics and genetic insights of Roifman syndrome but does not provide any evidence about the use of growth hormone therapy to address growth retardation.

[PMID:37666272] [NO_EVIDENCE] Roifman syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia, immunodeficiency, and retinal dystrophy. --- Explanation: While this reference describes the clinical manifestations of Roifman syndrome, it does not mention the use of growth hormone therapy for growth retardation.


MAXO:0000077

[PMID:21910238] [PARTIAL] The results confirmed a stable pattern of intellectual disability, and indicated that Roifman syndrome may be associated with major structural neuro-anatomical abnormalities. --- Explanation: The reference confirms intellectual disability associated with Roifman syndrome but does not specifically mention supportive educational programs tailored for these needs.

[PMID:28623346] [PARTIAL] Whole exome sequencing revealed KMT2A-associated Wiedemann-Steiner syndrome in one sibling pair and their mother. In the other sibling pair, targeted testing of the known disease gene for Roifman syndrome (RNU4ATAC) provided a definite diagnosis. --- Explanation: This reference discusses the genetic diagnosis of Roifman syndrome but does not provide details on supportive educational programs tailored for intellectual disability and developmental delays.


MAXO:0000004

[PMID:35450878] [REFUTE] Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency. --- Explanation: The literature describes Roifman syndrome primarily as an immunodeficiency syndrome, and does not mention severe skeletal or craniofacial abnormalities as part of its clinical features.


HGNC.SYMBOL:RNU4ATAC

[PMID:26522830] [SUPPORT] Roifman Syndrome is a rare congenital disorder... Targeted sequencing confirms allele segregation in six cases from four unrelated families. --- Explanation: This study confirms that Roifman Syndrome is associated with compound heterozygous mutations in the RNU4ATAC gene, which is inherited in an autosomal recessive manner.

[PMID:35450878] [SUPPORT] Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency. --- Explanation: This literature explicitly mentions that Roifman syndrome is inherited in an autosomal recessive manner.

[PMID:37225827] [SUPPORT] All patients had biallelic RNU4ATAC variants. --- Explanation: This study confirms that Roifman syndrome patients have biallelic (autosomal recessive) variants in the RNU4ATAC gene.


MONDO:0014658

[PMID:38993719] [SUPPORT] We administered GH therapy for a markedly short stature. --- Explanation: Case report explicitly notes markedly short stature in a patient with SADDAN.


MONDO:0014658

[PMID:24352917] [SUPPORT] Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is an extremely rare severe skeletal dysplasia characterized by significant developmental delay, brain structural abnormalities, hearing loss, and acanthosis nigricans. --- Explanation: The abstract states SADDAN is characterized by significant developmental delay.


MONDO:0014658

[PMID:24352917] [SUPPORT] Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is an extremely rare severe skeletal dysplasia characterized by significant developmental delay, brain structural abnormalities, hearing loss, and acanthosis nigricans. --- Explanation: The abstract lists acanthosis nigricans as a defining feature of SADDAN.

[PMID:10377013] [SUPPORT] In addition to skeletal dysplasia, progressive acanthosis nigricans, and central nervous system structural anomalies, seizures and severe developmental delays are observed in surviving SADDAN patients. --- Explanation: The phenotypic analysis reports progressive acanthosis nigricans in SADDAN.


MONDO:0014658

[PMID:10377013] [SUPPORT] In addition to skeletal dysplasia, progressive acanthosis nigricans, and central nervous system structural anomalies, seizures and severe developmental delays are observed in surviving SADDAN patients. --- Explanation: The phenotypic analysis reports seizures in SADDAN.


MONDO:0014658

[PMID:24352917] [SUPPORT] Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is an extremely rare severe skeletal dysplasia characterized by significant developmental delay, brain structural abnormalities, hearing loss, and acanthosis nigricans. --- Explanation: The abstract lists hearing loss as a characteristic feature of SADDAN.


MONDO:0014658

[PMID:19039991] [SUPPORT] severe central nervous system structural abnormalities, consisting of the absence of right cerebral hemisphere (hydranencephaly), ventricular dilatation, both indicating congenital brain malformation, and porencephaly indicating destructive brain damages. --- Explanation: Case report describes hydranencephaly in a SADDAN patient.


MONDO:0014658

[PMID:19039991] [SUPPORT] severe central nervous system structural abnormalities, consisting of the absence of right cerebral hemisphere (hydranencephaly), ventricular dilatation, both indicating congenital brain malformation, and porencephaly indicating destructive brain damages. --- Explanation: Case report notes ventricular dilatation (ventriculomegaly) in SADDAN.


MONDO:0014658

[PMID:10377013] [SUPPORT] Other unusual bone deformities, such as femoral bowing with reverse (i.e., posterior apex) tibial and fibular bowing and "ram's horn" bowing of the clavicle, are also seen in some patients. --- Explanation: The phenotypic analysis reports femoral bowing in SADDAN.


MONDO:0014658

[PMID:10377013] [SUPPORT] Other unusual bone deformities, such as femoral bowing with reverse (i.e., posterior apex) tibial and fibular bowing and "ram's horn" bowing of the clavicle, are also seen in some patients. --- Explanation: The phenotypic analysis reports tibial bowing in SADDAN.