MONDO:0015346

[PMID:8270934] [SUPPORT] Brief, typical absences occur with rapid eyelid myoclonia associated with retropulsive movements of the eyeballs and occasionally of the head. The seizures are of shorter duration than in childhood absence epilepsy, and are accompanied by less profound impairment of consciousness. --- Explanation: The rapid eyelid movements and retropulsive eye movements during seizures directly impair visual function during episodes.

[PMID:32554361] [SUPPORT] Jeavons syndrome (JS) is mainly characterized by eyelid myoclonia with or without absences. --- Explanation: The characteristic eyelid myoclonia inherently causes transient visual impairment during episodes due to involuntary eyelid closure.


MONDO:0015346

[PMID:21729035] [INDIRECT EVIDENCE] [PARTIAL] We observed two neurophysiologic findings in JS: (1) focal interictal EDs from posterior head region; and (2) predominant focal posterior ictal EDs preceding generalized EDs. --- Explanation: While the study supports an increased excitability of neurons in response to visual stimuli (such as photic stimulation), it does not specifically identify excitatory glutamatergic neurons as the key cell type involved.

[PMID:31444362] [INDIRECT EVIDENCE] [NO_EVIDENCE] The transition from a preictal state to a generalized seizure leads to an abrupt increase in neural activity and connectivity, which is accompanied by a strong alteration in glia-neuron interactions and a massive increase in extracellular glutamate. --- Explanation: This study discusses neural activity and connectivity alterations and increased extracellular glutamate during seizures but does not specifically associate these findings with Jeavons Syndrome.


MONDO:0015346


MONDO:0015346

[PMID:21729035] [INDIRECT EVIDENCE] [PARTIAL] JS has been proposed as idiopathic generalized epilepsy (IGE) because of normal posterior dominant background activity and paroxysmal generalized ictal epileptiform discharges (EDs). However, we noticed subtle occipital EDs preceding EM and interictal posterior EDs using digital video-EEG... Further clinical observations of seizures induced by eye closure, photic stimulation, and hyperventilation along with EEG paroxysms would raise the possibility of the occipital cortex initiating generalized epilepsy network involving the brainstem, and thalamocortical and transcortical pathways in JS. --- Explanation: The literature indicates involvement of the occipital cortex and mentions generalized epilepsy networks, which may include the thalamus. However, it does not explicitly support the claim that disruptions in the visual cortex and thalamus are the predominant mechanisms in Jeavons Syndrome.

[PMID:29880477] [INDIRECT EVIDENCE] [NO_EVIDENCE] Largely accepted in the literature is the role the interconnections between the thalamus and cortex play in generalized epilepsy. However, thalamocortical involvement is less understood in focal epilepsy in terms of the effect of seizures on thalamocortical circuitry in the developing brain and subsequent cognitive outcome. --- Explanation: This study discusses the role of thalamocortical connections in generalized and focal epilepsy but does not provide specific information on Jeavons Syndrome or its mechanisms.


MAXO:0000058

[PMID:6771426] [PARTIAL] Valproic acid, used alone or in combination with other anticonvulsants in 100 children with epilepsy, improved seizure control in all age groups. --- Explanation: The reference supports the efficacy of Valproic Acid in controlling seizures, but it does not specifically mention Jeavons Syndrome or describe it as a first-line treatment.

[PMID:11393330] [PARTIAL] Valproic acid controls absences in 75% of patients and also GTCS (70%) and myoclonic jerks (75%); however, it may be undesirable for some women. --- Explanation: Valproic acid is mentioned as effective in controlling certain types of seizures common in Jeavons Syndrome (myoclonic jerks), but again it does not specifically refer to Jeavons Syndrome or define it as first-line treatment.


CHEBI:39867

[PMID:6771426] [INDIRECT EVIDENCE] [PARTIAL] Valproic acid, used alone or in combination with other anticonvulsants in 100 children with epilepsy, improved seizure control in all age groups. --- Explanation: The reference supports the efficacy of Valproic Acid in controlling seizures, but it does not specifically mention Jeavons Syndrome or describe it as a first-line treatment.

[PMID:11393330] [INDIRECT EVIDENCE] [PARTIAL] Valproic acid controls absences in 75% of patients and also GTCS (70%) and myoclonic jerks (75%); however, it may be undesirable for some women. --- Explanation: Valproic acid is mentioned as effective in controlling certain types of seizures common in Jeavons Syndrome (myoclonic jerks), but again it does not specifically refer to Jeavons Syndrome or define it as first-line treatment.


MAXO:0000058

[PMID:17627674] [PARTIAL] Ethosuximide has a narrow therapeutic profile. It is the drug of choice in the monotherapy or combination therapy of children with generalized absence (petit mal) epilepsy. --- Explanation: The reference supports the use of ethosuximide as a treatment for generalized absence epilepsy, which is related to Jeavons syndrome. However, it does not provide specific evidence for its use as an alternative or adjunctive therapy specifically for Jeavons syndrome.


CHEBI:4887

[PMID:17627674] [INDIRECT EVIDENCE] [PARTIAL] Ethosuximide has a narrow therapeutic profile. It is the drug of choice in the monotherapy or combination therapy of children with generalized absence (petit mal) epilepsy. --- Explanation: The reference supports the use of ethosuximide as a treatment for generalized absence epilepsy, which is related to Jeavons syndrome. However, it does not provide specific evidence for its use as an alternative or adjunctive therapy specifically for Jeavons syndrome.


MAXO:0000058

[PMID:24798222] [SUPPORT] This case together with relevant literature data supports the view that the use of levetiracetam might be of benefit for female patients with Jeavons syndrome. --- Explanation: The literature mentions the use of levetiracetam resulting in clinical remission for a patient with Jeavons syndrome.

[PMID:20486734] [SUPPORT] The efficacy of levetiracetam as an adjunctive therapy and as monotherapy for generalized and partial childhood epilepsies and for some types of specific epileptic syndromes of infancy and childhood (such as juvenile myoclonic epilepsy, benign rolandic epilepsy, and Jeavon syndrome) has been demonstrated. --- Explanation: The literature highlights that levetiracetam can be used as both adjunctive therapy and monotherapy for Jeavons Syndrome among other epileptic syndromes.


CHEBI:6437

[PMID:24798222] [INDIRECT EVIDENCE] [SUPPORT] This case together with relevant literature data supports the view that the use of levetiracetam might be of benefit for female patients with Jeavons syndrome. --- Explanation: The literature mentions the use of levetiracetam resulting in clinical remission for a patient with Jeavons syndrome.

[PMID:20486734] [INDIRECT EVIDENCE] [SUPPORT] The efficacy of levetiracetam as an adjunctive therapy and as monotherapy for generalized and partial childhood epilepsies and for some types of specific epileptic syndromes of infancy and childhood (such as juvenile myoclonic epilepsy, benign rolandic epilepsy, and Jeavon syndrome) has been demonstrated. --- Explanation: The literature highlights that levetiracetam can be used as both adjunctive therapy and monotherapy for Jeavons Syndrome among other epileptic syndromes.


MAXO:0001014

[PMID:14706045] [PARTIAL] Visually provoked seizures, in particular, can be prevented or treated by avoiding or altering the triggering stimulus. Apart from individual preventive measures (use of specific television or video screens, colored glasses, etc.), prevention and warning on a larger scale are helpful. --- Explanation: The literature mentions that avoidance of visually provoking stimuli, like flickering lights, can help in managing photosensitive seizures, though it does not specifically mention Jeavons Syndrome.

[PMID:22946728] [PARTIAL] Recognized reflex seizure triggers are usually sensory and visual, such as television, discotheques, and video games. --- Explanation: This article suggests that visually evoked seizures can be triggered by stimuli like flickering lights, but it does not specifically address Jeavons Syndrome.

[PMID:32861158] [SUPPORT] Spikes/spike-waves time-locked to the flash frequency during intermittent light stimulation in Jeavons syndrome. --- Explanation: This directly supports that photic stimulation, such as flickering lights, can trigger seizures in patients with Jeavons Syndrome.

[PMID:29555355] [SUPPORT] Self-induced seizures were predominantly eyelid myoclonia +/- absences... EEG demonstrated a normal background with 3-4 Hz spike waves +/- polyspike waves as well as a photoparoxysmal response. --- Explanation: This reference indicates that photic stimulation can induce seizures in patients with Jeavons Syndrome, thus supporting the need to avoid such stimuli.


MAXO:0001014

[PMID:32861158] [NO_EVIDENCE] Spikes/spike-waves time-locked to the flash frequency during intermittent light stimulation in Jeavons syndrome --- Explanation: The focus is on the relationship between light stimulation and EEG patterns in Jeavons syndrome, with no mention of avoidance of triggers as a treatment method.


MAXO:0000950

[PMID:14706045] [NO_EVIDENCE] Visually provoked seizures, in particular, can be prevented or treated by avoiding or altering the triggering stimulus. Apart from individual preventive measures (use of specific television or video screens, colored glasses, etc.), prevention and warning on a larger scale are helpful. --- Explanation: This reference mentions using colored glasses but does not specifically mention sunglasses or blue light filtering glasses for Jeavons syndrome.

[PMID:30082241] [NO_EVIDENCE] We reviewed and described the epilepsy history, antiepileptic drug trials, and response to treatments. --- Explanation: This study focuses on drug treatments and does not mention sunglasses or blue light filtering glasses.

[PMID:26552567] [NO_EVIDENCE] Jeavons syndrome as an occipital cortex initiated generalized epilepsy. --- Explanation: The reference discusses the occipital cortex's role in Jeavons syndrome but does not mention sunglasses or blue light filtering glasses as a treatment.

[PMID:32861158] [NO_EVIDENCE] Spikes/spike-waves time-locked to the flash frequency during intermittent light stimulation in Jeavons syndrome. --- Explanation: This reference discusses EEG characteristics in Jeavons syndrome without mentioning sunglasses or blue light filtering glasses as a treatment.


HGNC.SYMBOL:SYNGAP1

[PMID:30541864] [SUPPORT] Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. --- Explanation: This large cohort study of 57 SYNGAP1 patients found 65% had eyelid myoclonia with absences, demonstrating strong overlap with Jeavons syndrome phenotype.

[PMID:34070602] [SUPPORT] Based on this, four genes could be associated to this syndrome (SYNGAP1, KIA02022/NEXMIF, RORB, and CHD2). --- Explanation: This review identifies SYNGAP1 as one of four candidate genes associated with eyelid myoclonia with absences (Jeavons syndrome).


HGNC.SYMBOL:NEXMIF

[PMID:34070602] [SUPPORT] Based on this, four genes could be associated to this syndrome (SYNGAP1, KIA02022/NEXMIF, RORB, and CHD2). --- Explanation: This review identifies NEXMIF (KIAA2022) as one of four candidate genes associated with eyelid myoclonia with absences (Jeavons syndrome).


HGNC.SYMBOL:RORB

[PMID:34070602] [SUPPORT] Based on this, four genes could be associated to this syndrome (SYNGAP1, KIA02022/NEXMIF, RORB, and CHD2). --- Explanation: This review identifies RORB as one of four candidate genes associated with eyelid myoclonia with absences (Jeavons syndrome).


HGNC.SYMBOL:CHD2

[PMID:26262932] [PARTIAL] Conversely, CHD2 could be responsible for a proper phenotype characterized by infantile-onset generalized epilepsy, intellectual disability, and photosensitivity, which might overlap with MAE, Lennox-Gastaut, Dravet, and Jeavons syndromes. --- Explanation: The literature indicates that CHD2 mutations may overlap with phenotypes seen in Jeavons Syndrome, but it does not specifically state a direct genetic association exclusive to Jeavons Syndrome.

[PMID:34070602] [SUPPORT] Based on this, four genes could be associated to this syndrome (SYNGAP1, KIA02022/NEXMIF, RORB, and CHD2). --- Explanation: This review identifies CHD2 as one of four candidate genes associated with eyelid myoclonia with absences (Jeavons syndrome).


HGNC.SYMBOL:CSNK2B


HGNC.SYMBOL:SLC2A1

[PMID:28419980] [REFUTE] We did not detect any pathogenic mutations in SLC2A1 in this cohort. Our data suggests that the frequency of GLUT1 mutations in NAFE is low. --- Explanation: The study indicates that no pathogenic mutations in SLC2A1 were found in the cohort, suggesting a low frequency of association with certain types of epilepsy, including Jeavons syndrome.


HGNC.SYMBOL:KCNB1

[PMID:34070602] [PARTIAL] Moreover, although there is not enough evidence yet to consider them as candidate for EMA, three more genes present also different alterations in some patients with clinical diagnosis of the disease (SLC2A1, NAA10, and KCNB1). --- Explanation: This review notes KCNB1 alterations in some EMA patients, though evidence is limited.


HGNC.SYMBOL:NAA10

[PMID:34070602] [PARTIAL] Moreover, although there is not enough evidence yet to consider them as candidate for EMA, three more genes present also different alterations in some patients with clinical diagnosis of the disease (SLC2A1, NAA10, and KCNB1). --- Explanation: This review notes NAA10 alterations in some EMA patients, though evidence is limited.


HGNC.SYMBOL:GABRA1

[PMID:14631097] [REFUTE] An Ala322Asp mutation in the GABRA1 gene was recently reported to be responsible for causing the autosomal dominant (AD) form of juvenile myoclonic epilepsy (JME) in a French-Canadian family. --- Explanation: The abstract does not mention Jeavons syndrome and focuses on juvenile myoclonic epilepsy related to GABRA1 mutations in a different population.

[PMID:30082241] [NO_EVIDENCE] We identified 30 patients who met the diagnostic criteria of Jeavons syndrome at a single institution... --- Explanation: The study focuses on clinical features and treatment response in Jeavons syndrome without mentioning GABRA1 or a genetic association.

[PMID:20074235] [NO_EVIDENCE] We have created the Epilepsy Genetic Association Database (epiGAD)... --- Explanation: The database mentions epilepsy genetic association studies but does not specifically address Jeavons syndrome or GABRA1.


XCO:0000284

[PMID:32861158] [SUPPORT] Spikes/spike-waves time-locked to the flash frequency during intermittent light stimulation in Jeavons syndrome. --- Explanation: This study indicates that flashing lights (photic stimulation) are associated with spikes and spike-waves in individuals with Jeavons syndrome, supporting the statement.

[PMID:14706039] [PARTIAL] In addition to this 'transversal' presence of the photosensitive trait across various epilepsy types and diseases, some syndromes in which all, or almost all, seizures are induced by photic stimuli seem to have sufficient specificity and may be considered as syndromes of pure reflex photosensitive epilepsy. --- Explanation: The study broadly discusses photosensitive epilepsy and its triggers but does not focus solely on Jeavons Syndrome. It implies a possible link but does not confirm the statement definitively.

[PMID:28508035] [NO_EVIDENCE] 'We propose that flashing light stimuli can be used as an experimental tool to investigate the visual function and plasticity of neuronal representations and perception after a critical period of neocortical plasticity.' --- Explanation: This study discusses the effects of flashing lights on visual perception and plasticity but does not directly relate to Jeavons Syndrome or its triggering factors.


XCO:0001069

[PMID:28314522] [SUPPORT] This study demonstrates that photosensitivity is enhanced after awakening from a short sleep following sleep deprivation. Thus, we recommend performing IPS after awakening to increase sensitivity to detect photoparoxysmal epileptiform discharges. --- Explanation: This reference indicates that sleep deprivation can enhance photosensitivity in patients, which can be a symptom exacerbation in conditions like Jeavons Syndrome, where photosensitivity is a significant factor.


MONDO:0018770

[PMID:17468754] [SUPPORT] often leads to death in infancy because of a severely constricted thoracic cage and respiratory insufficiency --- Explanation: Confirms constricted thorax as the cardinal feature causing respiratory failure and infant mortality in JATD.

[PMID:19442771] [SUPPORT] Jeune asphyxiating thoracic dystrophy (ATD) is an autosomal-recessive chondrodysplasia characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and trident acetabular roof. --- Explanation: Lists narrow thorax as a defining feature of JATD.


MONDO:0018770

[PMID:23339108] [SUPPORT] Asphyxiating Thoracic Dysplasia (ATD) belongs to the short rib polydactyly group and is characterized by a narrow thorax, short long bones and trident acetabular roof. --- Explanation: Confirms short ribs as a defining feature of JATD within the short rib polydactyly group.


MONDO:0018770

[PMID:19442771] [SUPPORT] characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and trident acetabular roof. --- Explanation: Lists short long bones as a characteristic feature of JATD.


MONDO:0018770

[PMID:17468754] [SUPPORT] retinal degeneration, cystic renal disease and polydactyly may be complicating features. --- Explanation: Lists polydactyly as a complicating feature of JATD.

[PMID:23456818] [SUPPORT] DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. --- Explanation: DYNC2H1 patients largely lack polydactyly, demonstrating an important genotype-phenotype correlation.


MONDO:0018770

[PMID:23339108] [SUPPORT] Renal and liver diseases occurred respectively in 17% and 22% of cases --- Explanation: Quantifies renal disease at 17% of postnatal JATD cases.


MONDO:0018770

[PMID:23339108] [SUPPORT] Renal and liver diseases occurred respectively in 17% and 22% of cases --- Explanation: Quantifies liver disease at 22% of postnatal JATD cases.


MONDO:0018770

[PMID:23339108] [SUPPORT] retinal alteration was present in 50% of cases aged more than 5 years. --- Explanation: Quantifies retinal involvement at 50% of JATD patients over age 5.

[PMID:17468754] [SUPPORT] retinal degeneration, cystic renal disease and polydactyly may be complicating features. --- Explanation: Lists retinal degeneration as a complicating feature of JATD.


MONDO:0018770

[PMID:23339108] [SUPPORT] pulmonary insufficiency was noted in 60% of cases, with tracheotomy requirement in five cases. --- Explanation: Quantifies pulmonary insufficiency at 60% of postnatal JATD cases.


MONDO:0018770

[PMID:17468754] [INDIRECT EVIDENCE] [SUPPORT] IFT80 mutations underlie a subset of Jeune asphyxiating thoracic dystrophy cases, establishing the first association of a defective intraflagellar transport (IFT) protein with human disease. --- Explanation: Landmark paper establishing the first link between IFT dysfunction and human skeletal ciliopathy.

[PMID:23339108] [INDIRECT EVIDENCE] [SUPPORT] To date, mutations in IFT80, DYNC2H1, TTC21B and WDR19 have been reported in ATD. The clinical and molecular heterogeneity leads to difficulties in the evaluation of the long-term prognosis. --- Explanation: Confirms multiple IFT/dynein genes are implicated in JATD, establishing genetic heterogeneity.


MONDO:0018770


MONDO:0018770

[PMID:19442771] [INDIRECT EVIDENCE] [SUPPORT] DYNC2H1 is a component of a cytoplasmic dynein complex and is directly involved in the generation and maintenance of cilia. --- Explanation: Confirms DYNC2H1 encodes a dynein-2 motor component required for cilium generation and maintenance.

[PMID:23456818] [INDIRECT EVIDENCE] [SUPPORT] Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations --- Explanation: Demonstrates that DYNC2H1 mutations cause retrograde IFT defects with accumulation of anterograde transport proteins at ciliary tips.


MONDO:0018770

[PMID:17468754] [INDIRECT EVIDENCE] [SUPPORT] Knockdown of ift80 in zebrafish resulted in cystic kidneys --- Explanation: Zebrafish ift80 knockdown recapitulates the renal cystic phenotype, confirming ciliary dysfunction causes renal cystogenesis.


MAXO:0000004

[PMID:25575358] [SUPPORT] Survival rate of the 22 patients was 68%. --- Explanation: Reports 68% survival rate with VEPTR surgical treatment.

[PMID:25575358] [SUPPORT] The survival rate in JS with surgery was nearly 70% (compared with 70% to 80% mortality without treatment) with less ventilator dependence. --- Explanation: Demonstrates dramatic improvement in survival with VEPTR surgery compared to untreated JATD.

[PMID:25575358] [SUPPORT] Average chest width increased from 121 to 168 mm at follow-up (P<0.001). --- Explanation: Quantifies the significant increase in thoracic dimensions achieved by VEPTR expansion surgery.


HGNC.SYMBOL:DYNC2H1 Mutations

[PMID:19442771] [SUPPORT] identified homozygous mutations in the cytoplasmic dynein 2 heavy chain 1 (DYNC2H1) gene in the affected children. --- Explanation: Identifies DYNC2H1 as a causative gene for JATD.

[PMID:23456818] [SUPPORT] We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. --- Explanation: Large cohort showing DYNC2H1 mutations in 41% of JATD patients, establishing it as the most common genetic cause.

[PMID:23456818] [SUPPORT] DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. --- Explanation: Important genotype-phenotype correlation showing DYNC2H1 patients have primarily skeletal disease.

[PMID:23339108] [SUPPORT] We identified DYNC2H1 mutations in 23 families (59%) and IFT80 mutations in two families (5%). --- Explanation: French cohort showing DYNC2H1 mutations in 59% of JATD families.


HGNC.SYMBOL:IFT80 Mutations

[PMID:17468754] [SUPPORT] We show that IFT80 mutations underlie a subset of Jeune asphyxiating thoracic dystrophy cases, establishing the first association of a defective intraflagellar transport (IFT) protein with human disease. --- Explanation: First identification of IFT80 as a causative gene for JATD.

[PMID:23339108] [SUPPORT] We identified DYNC2H1 mutations in 23 families (59%) and IFT80 mutations in two families (5%). --- Explanation: Confirms IFT80 is a rare cause of JATD at 5% of families.


HGNC.SYMBOL:IFT140 Mutations


HGNC.SYMBOL:WDR19 Mutations


MONDO:0018772

[PMID:40537162] [SUPPORT] Classic defects include hypoplasia of the cerebellar vermis, thickened cerebellar peduncles, and deepened interpeduncular fossa, which is regarded as a "molar tooth" sign. --- Explanation: The molar tooth sign is a classic diagnostic feature of JS.


MONDO:0018772

[PMID:40537162] [SUPPORT] Classic defects include hypoplasia of the cerebellar vermis, thickened cerebellar peduncles, and deepened interpeduncular fossa, which is regarded as a "molar tooth" sign. --- Explanation: This review identifies cerebellar vermis hypoplasia as a classic defect in JS.


MONDO:0018772

[PMID:36803942] [SUPPORT] Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes. --- Explanation: Hypotonia is listed as a characteristic feature of JS.


MONDO:0018772

[PMID:36803942] [SUPPORT] Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes. --- Explanation: Ataxia is described among characteristic features of JS.


MONDO:0018772

[PMID:36803942] [SUPPORT] Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes. --- Explanation: Intellectual disability is noted as a characteristic feature.


MONDO:0018772

[PMID:38502237] [SUPPORT] Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and a peculiar cerebellar and brainstem malformation, the "molar tooth sign." --- Explanation: Psychomotor delay supports global developmental delay in JS.


MONDO:0018772

[PMID:35860112] [SUPPORT] Clinical features can be noticed shortly after birth that includes hypotonia episodic tachypnea and apnea that may be followed by developmental delays and speech apraxia. --- Explanation: This case report notes speech apraxia in JS.


MONDO:0018772

[PMID:38502237] [SUPPORT] Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and a peculiar cerebellar and brainstem malformation, the "molar tooth sign." --- Explanation: Abnormal ocular movements are a defining neurologic-ophthalmologic feature.


MONDO:0018772

[PMID:36803942] [SUPPORT] Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes. --- Explanation: Oculomotor apraxia is listed among characteristic JS features.


MONDO:0018772

[PMID:37547106] [SUPPORT] Thirty-four (94.44%) cases had developmental delay, one patient (2.78%) had strabismus, and one patient (2.78%) had intermittent dizziness. --- Explanation: This cohort reports strabismus in a small subset of JS patients.


MONDO:0018772

[PMID:36803942] [SUPPORT] Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes. --- Explanation: Retinal dystrophy is cited as a characteristic feature.


MONDO:0018772

[PMID:36803942] [SUPPORT] Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes. --- Explanation: Respiratory system abnormalities are reported among characteristic features.


MONDO:0018772

[PMID:35860112] [SUPPORT] Clinical features can be noticed shortly after birth that includes hypotonia episodic tachypnea and apnea that may be followed by developmental delays and speech apraxia. --- Explanation: This case report describes episodic tachypnea in JS.


MONDO:0018772

[PMID:35860112] [SUPPORT] Clinical features can be noticed shortly after birth that includes hypotonia episodic tachypnea and apnea that may be followed by developmental delays and speech apraxia. --- Explanation: This case report describes apnea in JS.


MONDO:0018772

[PMID:36803942] [SUPPORT] Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes. --- Explanation: Renal cysts are reported as part of the JS phenotype spectrum.


MONDO:0018772

[PMID:36580738] [SUPPORT] Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients. --- Explanation: This cohort reports nephronophthisis as kidney involvement in JS.


MONDO:0018772

[PMID:36803942] [SUPPORT] Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes. --- Explanation: Hepatic fibrosis is reported among characteristic JS features.


MONDO:0018772

[PMID:36580738] [SUPPORT] Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients. --- Explanation: Portal hypertension was reported as a liver involvement in this cohort.


MONDO:0018772

[PMID:36580738] [SUPPORT] Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients. --- Explanation: Esophageal varices were observed in JS patients in this cohort.


MONDO:0018772

[PMID:36803942] [SUPPORT] Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes. --- Explanation: Skeletal changes are included in the JS phenotype spectrum.


MONDO:0018772

[PMID:35602833] [SUPPORT] Here, we present the case of a 20-year-old patient who presented with a new onset of dysphagia that led to a diagnosis of JS. --- Explanation: This adult JS case report highlights dysphagia as a presenting symptom.


MONDO:0018772

[PMID:33717386] [SUPPORT] presenting with dyspnea, cyanosis, signs of respiratory distress and seizures. --- Explanation: This neonatal case report documents seizures in JS.


MONDO:0018772

[PMID:36052101] [SUPPORT] was referred to the Sleep Unit because spells of apnea while sleeping. --- Explanation: This case report describes sleep apnea in a JS patient.


MONDO:0018772

[PMID:38013309] [SUPPORT] Resection was performed to correct the polydactyly. --- Explanation: This JS case report documents polydactyly requiring surgical correction.


MONDO:0018772

[PMID:38502237] [INDIRECT EVIDENCE] [SUPPORT] Over 40 causative genes have been reported, all encoding for proteins implicated in the structure or functioning of the primary cilium, a subcellular organelle widely present in embryonic and adult tissues. --- Explanation: JS genes encode primary cilium components, supporting disrupted cilium assembly.

[PMID:41165761] [INDIRECT EVIDENCE] [SUPPORT] B9 proteins localized to centrioles prior to ciliogenesis, where they facilitated the initiation of ciliogenesis. --- Explanation: This supports impaired ciliogenesis initiation as a core ciliary assembly defect.


MONDO:0018772

[PMID:38502237] [INDIRECT EVIDENCE] [SUPPORT] In addition, analysis of primary cilium count and morphology showed notable ciliary defects in all differentiating JS patient-derived iPSCs compared to controls. --- Explanation: Patient-derived cells show abnormal primary cilium structure.

[PMID:36802443] [INDIRECT EVIDENCE] [SUPPORT] Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish. --- Explanation: Zebrafish models demonstrate in vivo ciliary defects consistent with abnormal cilium organization.

[PMID:39400299] [INDIRECT EVIDENCE] [SUPPORT] We found that JBTS mutants have altered primary cilia throughout the brain. --- Explanation: Zebrafish JBTS mutants show altered primary cilia in brain tissue.

[PMID:40951761] [INDIRECT EVIDENCE] [SUPPORT] The patient-derived fibroblasts exhibited reduced primary cilia length and altered distribution of PCM1. --- Explanation: KIAA0586/TALPID3 variants are associated with reduced cilia length.


MONDO:0018772

[PMID:33717386] [INDIRECT EVIDENCE] [SUPPORT] Recently, it has been proposed that CEP290 gene product may also play a role in the microtubule-based ciliary transport, in the vesicle transport, the development and maintenance of the cilium --- Explanation: CEP290 dysfunction is linked to impaired intraciliary transport and cilium maintenance.


MAXO:0000950

[PMID:36484066] [SUPPORT] Patient was managed conservatively with symptomatic treatment. --- Explanation: This case report indicates conservative symptomatic management in JS.


MAXO:0000011

[PMID:37288221] [SUPPORT] All patients received physical, occupational, and speech-language-hearing therapy, depending on their symptoms and conditions. --- Explanation: This case series describes physical therapy in JS rehabilitation.


MAXO:0001351

[PMID:37288221] [SUPPORT] All patients received physical, occupational, and speech-language-hearing therapy, depending on their symptoms and conditions. --- Explanation: This case series describes occupational therapy in JS rehabilitation.


MAXO:0000930

[PMID:37288221] [SUPPORT] All patients received physical, occupational, and speech-language-hearing therapy, depending on their symptoms and conditions. --- Explanation: This case series describes speech-language therapy in JS rehabilitation.


MAXO:0000482

[PMID:37288221] [SUPPORT] For hypotonia and ataxia, an orthotic intervention was considered in all three cases, and foot or ankle-foot orthoses were used in two cases. --- Explanation: This case series reports orthotic device usage to address hypotonia and ataxia.


MAXO:0000079

[PMID:37490694] [SUPPORT] The early diagnosis of Joubert syndrome is reflected in better pediatric follow-up, which impacts its prognosis and the possibility of improving the patient's quality of life with a multidisciplinary management and genetic counseling. --- Explanation: The case report highlights genetic counseling as part of care that improves quality of life.


MAXO:0001175

[PMID:37965976] [SUPPORT] LT should be considered an effective treatment for COACH syndrome in patients with severe portal hypertension. --- Explanation: The review concludes that liver transplantation is effective for JS patients with congenital hepatic fibrosis and portal hypertension.


hgnc:25801

[PMID:36580738] [SUPPORT] The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. --- Explanation: This cohort identifies CPLANE1 among the most common JS genes.

[PMID:35092359] [SUPPORT] We identified two novel heterozygous variants of CPLANE1 in the proband first, including c.4459del (frameshift variant) and c.7534-14G > A (intronic variant). --- Explanation: This study reports pathogenic CPLANE1 variants in a JS patient.

[PMID:39725884] [SUPPORT] revealing a pair of compound heterozygous CPLANE1 variants --- Explanation: This prenatal JS case report links CPLANE1 variants to diagnosis.

[PMID:33794348] [SUPPORT] The whole exome sequencing identified a novel compound heterozygous variation in the CPLANE1 gene related with Joubert syndrome --- Explanation: This prenatal case report identifies CPLANE1 variants causing JS.


hgnc:29021

[PMID:36580738] [SUPPORT] The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. --- Explanation: This cohort identifies CEP290 as a common JS gene.

[PMID:35238134] [SUPPORT] On the other hand, individuals with causal variants in the CEP290 or AHI1 need a closer surveillance for retinal dystrophy and, in case of CEP290, also for chronic kidney disease. --- Explanation: CEP290 variants are linked to retinal dystrophy risk and chronic kidney disease surveillance.

[PMID:33717386] [SUPPORT] Genome sequencing revealed a mutation involving the CEP290 gene that ultimately confirmed the diagnosis of Joubert syndrome. --- Explanation: This case report identifies CEP290 mutation as the cause of JS.


hgnc:28396

[PMID:36580738] [SUPPORT] The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. --- Explanation: This cohort identifies TMEM67 as a common JS gene.

[PMID:35238134] [SUPPORT] For instance, JS individuals harboring pathogenic variants in TMEM67 have a significantly higher risk of liver fibrosis, while pathogenic variants in NPHP1, RPGRIP1L, and TMEM237 are frequently associated to JS with renal involvement, requiring a closer monitoring of liver parameters, or renal functioning. --- Explanation: TMEM67 variants are associated with increased liver fibrosis risk in JS.

[PMID:39027323] [SUPPORT] The diagnosis of autosomal recessive Joubert syndrome type 6 due to homozygous pathogenic variant c.725A > G p. (Asn242Ser) in TMEM67 gene was confirmed by whole exome sequencing. --- Explanation: This JS type 6 case confirms a pathogenic TMEM67 variant.

[PMID:39849212] [SUPPORT] Whole Exome Sequencing (WES), performed via buccal swab, showed biallelic pathogenic variants at NM_153704.6:c.2086 C > T (NP_714915.3:p.Leu696Phe) and NM_153704.6:c.431del (NP_714915.3:p.Leu144CysfsTer19) in TMEM67, which are associated with Joubert Syndrome 6 (OMIM:610688) in a compound heterozygous state. --- Explanation: This case report identifies biallelic TMEM67 variants associated with Joubert syndrome 6.


hgnc:21575

[PMID:35238134] [SUPPORT] On the other hand, individuals with causal variants in the CEP290 or AHI1 need a closer surveillance for retinal dystrophy and, in case of CEP290, also for chronic kidney disease. --- Explanation: This review notes AHI1 variants in JS with retinal dystrophy risk.

[PMID:33777383] [SUPPORT] Variants in AHI1 account for ∼7% of Joubert syndrome cases and are associated either with ‘pure’ Joubert syndrome, or Joubert syndrome plus renal and/or retinal disease. --- Explanation: This adult JS case report summarizes AHI1 contribution to JS cases.


hgnc:20730

[PMID:36580738] [SUPPORT] The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. --- Explanation: This cohort reports ARMC9 among causative JS genes.


hgnc:12370

[PMID:36580738] [SUPPORT] The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. --- Explanation: This cohort reports CEP41 among causative JS genes.


hgnc:26193

[PMID:36580738] [SUPPORT] The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. --- Explanation: This cohort reports CSPP1 among causative JS genes.

[PMID:40898267] [SUPPORT] Pathogenic CSPP1 variants account for approximately 3% of Joubert syndrome cases. --- Explanation: This case report notes CSPP1 pathogenic variants contribute to JS, supporting CSPP1 as a causative gene.


hgnc:26558

[PMID:36580738] [SUPPORT] The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. --- Explanation: This cohort reports HYLS1 among causative JS genes.


hgnc:29068

[PMID:36580738] [SUPPORT] The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. --- Explanation: This cohort reports KATNIP among causative JS genes.


hgnc:19960

[PMID:36580738] [SUPPORT] The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. --- Explanation: This cohort reports KIAA0586 among causative JS genes.

[PMID:36788019] [SUPPORT] Two recurrent variants (MKS1 c.1476T>G and KIAA0586 c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants. --- Explanation: This study identifies recurrent KIAA0586 variants in JS cohorts.

[PMID:40951761] [SUPPORT] Variants in KIAA0586/TALPID3 are associated with the ciliopathy Joubert syndrome (JS), which is a genetically heterogeneous disorder. --- Explanation: This study links KIAA0586/TALPID3 variants to JS.

[PMID:41020477] [SUPPORT] JBTS23, a subtype of Joubert syndrome, is caused by variations in the KIAA0586 gene. --- Explanation: This report identifies pathogenic KIAA0586 variants in a JS subtype, supporting causative association.


hgnc:30497

[PMID:36580738] [SUPPORT] The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. --- Explanation: This cohort reports KIF7 among causative JS genes.


hgnc:29168

[PMID:36580738] [SUPPORT] The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. --- Explanation: This cohort reports RPGRIP1L among causative JS genes.

[PMID:38013309] [SUPPORT] Joubert syndrome 7 is caused by mutations in the RPGRIP1L gene. --- Explanation: This case report highlights RPGRIP1L as a JS gene.

[PMID:37547106] [SUPPORT] RPGRIP1l: c.1351-11A > G; CEP120: c.214 C > T(p.Arg72Cys). --- Explanation: This cohort reports RPGRIP1L variants in JS.

[PMID:37993833] [SUPPORT] Genetic analysis showed novel compound heterozygous mutations in the RPGRIP1L gene [p.L447fs*7(p.Leu447fsTer7) and p.G908V (p.Gly908Val)]. --- Explanation: This case report identifies RPGRIP1L mutations in JS with oculorenal involvement.


hgnc:7121

[PMID:36788019] [SUPPORT] Two recurrent variants (MKS1 c.1476T>G and KIAA0586 c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants. --- Explanation: This study reports recurrent MKS1 variants in JS cohorts.


hgnc:29253

[PMID:36319078] [SUPPORT] cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A. --- Explanation: This study focuses on CC2D2A-related JS with pathogenic variants.


hgnc:2567

[PMID:36704348] [SUPPORT] We identified a novel non-sense variant in the OFD1 gene, OFD1 (NM_003611.3): c.2848A>T (p.Lys950Ter). --- Explanation: This study reports a pathogenic OFD1 variant in JS.


hgnc:26113

[PMID:34980503] [SUPPORT] Joubert syndrome attributed to variants in the TCTN1 (NM_001082538.2) gene has been only described in two reports. --- Explanation: This case report supports TCTN1 as a JS gene.


hgnc:26690

[PMID:37547106] [SUPPORT] RPGRIP1l: c.1351-11A > G; CEP120: c.214 C > T(p.Arg72Cys). --- Explanation: This cohort reports a CEP120 variant associated with JS.


hgnc:21653

[PMID:37227088] [SUPPORT] Our data nominates TOPORS as a novel causal gene for JBTS --- Explanation: This study identifies TOPORS as a novel JS gene.


MONDO:0018772

[PMID:33717386] [SUPPORT] elevated levels of urea and creatinine were detected --- Explanation: This neonatal JS case report documents elevated urea.


MONDO:0018772

[PMID:33717386] [SUPPORT] elevated levels of urea and creatinine were detected --- Explanation: This neonatal JS case report documents elevated creatinine.

[PMID:33777383] [SUPPORT] Her eGFR at the age of 51 years was 57 mL/min/1.73 m2 --- Explanation: This adult JS case report provides serum creatinine levels with reduced eGFR.


MONDO:0017612

[PMID:20301304] [SUPPORT] Junctional epidermolysis bullosa (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma --- Explanation: GeneReviews confirms skin blistering with minimal trauma as the defining feature of JEB.

[PMID:32973163] [SUPPORT] Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by often minimal trauma --- Explanation: Confirms mucocutaneous fragility and blister formation as hallmark features of EB.


MONDO:0017612

[PMID:20301304] [SUPPORT] Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway --- Explanation: Confirms granulation tissue formation in periorificial areas as a feature of JEB.


MONDO:0017612

[PMID:20301304] [SUPPORT] Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia --- Explanation: GeneReviews confirms nail dystrophy as a shared feature across JEB and other EB forms.


MONDO:0017612

[PMID:20301304] [SUPPORT] regular dental care --- Explanation: GeneReviews recommends regular dental care for JEB patients, indicating dental complications from enamel involvement.

[PMID:19700011] [SUPPORT] Some epidermolysis bullosa subtypes are at risk for severe injury of the bone marrow, musculoskeletal system, heart, kidney, and teeth --- Explanation: Confirms teeth involvement as an extracutaneous complication of EB subtypes including JEB.


MONDO:0017612

[PMID:20301304] [SUPPORT] regular dental care --- Explanation: GeneReviews recommends regular dental care as part of JEB management, indicating dental complications including caries.

[PMID:19700011] [SUPPORT] Some epidermolysis bullosa subtypes are at risk for severe injury of the bone marrow, musculoskeletal system, heart, kidney, and teeth --- Explanation: Confirms teeth involvement as an extracutaneous EB complication.


MONDO:0017612

[PMID:20301304] [SUPPORT] Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia --- Explanation: GeneReviews confirms scarring alopecia as a shared feature of JEB.


MONDO:0017612

[PMID:20301304] [SUPPORT] granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway --- Explanation: Upper airway involvement in JEB causes laryngeal complications including hoarse cry.


MONDO:0017612

[PMID:20301304] [SUPPORT] nutritional support including feeding gastrostomy when necessary; calcium, vitamin D, zinc, and iron supplements --- Explanation: Need for nutritional support and gastrostomy indicates failure to thrive as a complication of JEB.


MONDO:0017612

[PMID:20301304] [SUPPORT] The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2 --- Explanation: ITGB4 mutations cause the JEB-PA subtype with pyloric atresia.


MONDO:0017612

[PMID:20301304] [SUPPORT] Congenital malformations of the urinary tract and bladder may also occur --- Explanation: GeneReviews confirms urinary tract and bladder involvement in JEB.


MONDO:0017612

[PMID:20301304] [SUPPORT] granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway --- Explanation: GeneReviews confirms upper airway involvement in JEB including granulation tissue formation, which can lead to respiratory compromise requiring tracheostomy.

[PMID:22512697] [SUPPORT] The causes of death were, in order of frequency: failure to thrive, respiratory failure, pneumonia, dehydration, anaemia, sepsis and euthanasia --- Explanation: Dutch EB Registry data confirms respiratory failure as a major cause of death in JEB-Herlitz.


MONDO:0017612

[PMID:20301304] [SUPPORT] Annual screening for iron-deficiency anemia, zinc deficiency, vitamin D deficiency --- Explanation: GeneReviews recommends annual screening for iron-deficiency anemia in JEB patients.


MONDO:0017612

[PMID:23076207] [INDIRECT EVIDENCE] [SUPPORT] Mutations in the LAMA3, LAMB3 and LAMC2 genes that encode the three constituent polypeptide chains, α3, β3 and γ2, abrogate or perturb the functions of laminin 332 --- Explanation: Confirms that mutations in laminin-332 genes abrogate or perturb protein function.

[PMID:23076207] [INDIRECT EVIDENCE] [SUPPORT] Laminin 332 is an essential component of the dermal-epidermal junction, a highly specialized basement membrane zone that attaches the epidermis to the dermis and thereby provides skin integrity and resistance to external mechanical forces --- Explanation: Confirms laminin-332 is essential for dermal-epidermal adhesion.


MONDO:0017612


MONDO:0017612

[PMID:20301304] [INDIRECT EVIDENCE] [SUPPORT] The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2 --- Explanation: Confirms COL17A1 as a causative gene for JEB.

[PMID:32973163] [INDIRECT EVIDENCE] [SUPPORT] pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion --- Explanation: Confirms EB is caused by mutations in genes encoding adhesion proteins.


MONDO:0017612

[PMID:20301304] [INDIRECT EVIDENCE] [SUPPORT] The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2 --- Explanation: Confirms ITGB4 as a causative gene for JEB.


MONDO:0017612

[PMID:32973163] [INDIRECT EVIDENCE] [SUPPORT] Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by often minimal trauma --- Explanation: Confirms that blister formation with minimal trauma is the defining feature of EB.

[PMID:23076207] [INDIRECT EVIDENCE] [SUPPORT] The phenotypic consequences are diminished dermal-epidermal adhesion and, as clinical symptoms, skin fragility and mechanically induced blistering --- Explanation: Confirms diminished adhesion causing skin fragility and blistering in JEB.


MONDO:0017612

[PMID:20301304] [INDIRECT EVIDENCE] [SUPPORT] Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway --- Explanation: Confirms granulation tissue formation in periorificial areas as a feature of JEB.

[PMID:12915477] [INDIRECT EVIDENCE] [SUPPORT] These studies show that the laminin alpha3a N-terminal domain is a key regulator of the granulation tissue response, with important implications not only in LOC but in a range of other clinical conditions associated with abnormal wound healing --- Explanation: LOC syndrome demonstrates that an N-terminal deletion of laminin alpha3a produces exuberant granulation tissue without generalized blistering, proving that granulation tissue in JEB reflects loss of laminin signaling rather than simply chronic wounding.

[PMID:12915477] [INDIRECT EVIDENCE] [SUPPORT] This protein is secreted only by the basal keratinocytes of stratified epithelia, implying that LOC is caused by dysfunction of keratinocyte-mesenchymal communication --- Explanation: The laminin alpha3a isoform mediates keratinocyte-mesenchymal signaling, and its dysfunction causes the granulation tissue phenotype.


MONDO:0017612

[PMID:23076207] [INDIRECT EVIDENCE] [SUPPORT] This article delineates the signs and symptoms of the different forms of JEB, the mutational spectrum, genotype-phenotype correlations as well as perspectives for future molecular therapies --- Explanation: Comprehensive review covering JEB signs and symptoms including dental involvement from basement membrane defects.


MAXO:0000950

[PMID:20301304] [SUPPORT] Lance and drain new blisters and dress with three layers (primary: non-adherent; secondary: for stability and protection; third: elastic properties to ensure integrity) --- Explanation: GeneReviews describes three-layer wound dressing protocol for JEB.

[PMID:32973163] [SUPPORT] multidisciplinary care is targeted towards minimizing the risk of blister formation, wound care, symptom relief and specific complications --- Explanation: Confirms wound care as a central component of EB management.


MAXO:0000088

[PMID:20301304] [SUPPORT] nutritional support including feeding gastrostomy when necessary; calcium, vitamin D, zinc, and iron supplements --- Explanation: GeneReviews confirms nutritional support including gastrostomy and supplementation as part of JEB management.


MAXO:0000004

[PMID:20301304] [SUPPORT] tracheostomy if appropriate --- Explanation: GeneReviews recommends tracheostomy when appropriate for airway involvement in JEB.


MAXO:0001001

[PMID:17115047] [SUPPORT] Epidermal stem cells from an adult patient affected by LAM5-beta3-deficient JEB were transduced with a retroviral vector expressing LAMB3 cDNA (encoding LAM5-beta3), and used to prepare genetically corrected cultured epidermal grafts --- Explanation: First demonstration of ex vivo gene therapy for JEB using LAMB3-corrected autologous epidermal stem cells.

[PMID:17115047] [SUPPORT] These data show that ex vivo gene therapy of JEB is feasible and leads to full functional correction of the disease --- Explanation: Confirms feasibility and full functional correction of JEB by ex vivo gene therapy.

[PMID:29144448] [SUPPORT] autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB --- Explanation: Landmark case demonstrating regeneration of entire body surface epidermis using transgenic stem cells in a child with JEB.

[PMID:34881838] [SUPPORT] We previously reported that genetically corrected autologous epidermal cultures regenerated almost an entire, fully functional epidermis on a child who had a devastating form of junctional epidermolysis bullosa. We now report long-term clinical outcomes in this patient --- Explanation: Five-year follow-up of the Hirsch 2017 patient confirms the transgenic epidermis remained stable and fully functional with no adverse events and normal sensory recovery.

[PMID:24511464] [SUPPORT] the regenerated transgenic epidermis was found to be fully functional and virtually indistinguishable from a normal control --- Explanation: Long-term (6.5-year) follow-up of the first Mavilio 2006 gene therapy patient showing stable, functional transgenic epidermis sustained by self-renewing epidermal stem cells.


MAXO:0000058

[PMID:36689495] [SUPPORT] Oleogel-S10 is the first therapy to demonstrate accelerated wound healing in EB --- Explanation: Phase III EASE trial confirms Oleogel-S10 (birch triterpenes) as the first therapy to demonstrate accelerated wound healing in EB.

[PMID:36689495] [SUPPORT] Oleogel-S10 resulted in 41·3% of patients with first complete target wound closure within 45 days, compared with 28·9% in the control gel arm --- Explanation: Quantitative efficacy data from the EASE trial showing significantly higher wound closure rates with birch triterpenes.


MAXO:0000950

[PMID:20301304] [SUPPORT] regular dental care --- Explanation: GeneReviews recommends regular dental care as part of JEB management.


MAXO:0000079

[PMID:20301304] [SUPPORT] each sib of an affected individual whose parents are both carriers has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier --- Explanation: Confirms autosomal recessive inheritance pattern and recurrence risk counseling.


HGNC.SYMBOL:LAMB3

[PMID:23076207] [SUPPORT] Mutations in the LAMA3, LAMB3 and LAMC2 genes that encode the three constituent polypeptide chains, α3, β3 and γ2, abrogate or perturb the functions of laminin 332 --- Explanation: Confirms LAMB3 mutations abrogate laminin-332 function causing JEB.

[PMID:19945616] [SUPPORT] this devastating condition is most often caused by homozygous null mutations in the genes LAMA3, LAMB3, or LAMC2, each encoding for 1 of the 3 chains of the heterotrimer laminin-332 --- Explanation: Confirms LAMB3 as one of the three genes most often mutated in JEB-Herlitz.


HGNC.SYMBOL:LAMA3

[PMID:19945616] [SUPPORT] this devastating condition is most often caused by homozygous null mutations in the genes LAMA3, LAMB3, or LAMC2, each encoding for 1 of the 3 chains of the heterotrimer laminin-332 --- Explanation: Confirms LAMA3 as a causative gene for JEB-Herlitz.


HGNC.SYMBOL:LAMC2

[PMID:19945616] [SUPPORT] this devastating condition is most often caused by homozygous null mutations in the genes LAMA3, LAMB3, or LAMC2, each encoding for 1 of the 3 chains of the heterotrimer laminin-332 --- Explanation: Confirms LAMC2 as a causative gene for JEB-Herlitz.


HGNC.SYMBOL:COL17A1

[PMID:20301304] [SUPPORT] The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2 --- Explanation: Confirms COL17A1 as a causative gene for JEB.

[PMID:9038345] [SUPPORT] the revertant mosaicism of a compound heterozygous proband with an autosomal recessive genodermatosis, generalized atrophic benign epidermolysis bullosa, is caused by mitotic gene conversion of one of the two mutated COL17A1 alleles --- Explanation: First demonstration that mitotic gene conversion of COL17A1 causes revertant mosaicism in JEB, producing clinically unaffected skin patches.

[PMID:9038345] [SUPPORT] Revertant mosaicism represents a way of natural gene therapy --- Explanation: Revertant patches represent natural somatic correction but remain localized and do not expand to correct the whole epidermis.


HGNC.SYMBOL:ITGA6

[PMID:32973163] [SUPPORT] pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion --- Explanation: EB consensus classification recognizes 16+ causative genes including ITGA6 encoding integrin alpha-6, part of the alpha6-beta4 heterodimer critical for hemidesmosome function.


HGNC.SYMBOL:ITGB4

[PMID:20301304] [SUPPORT] The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2 --- Explanation: Confirms ITGB4 as a causative gene for JEB.


MONDO:0017380

[PMID:22171123] [SUPPORT] Juvenile polyposis syndrome is a rare autosomal dominant syndrome characterized by multiple distinct juvenile polyps in the gastrointestinal tract and an increased risk of colorectal cancer. --- Explanation: This directly supports juvenile GI polyposis as the obligate defining phenotype of JPS.


MONDO:0017380

[PMID:7881943] [SUPPORT] The more common form of juvenile polyposis (affecting the colon, stomach and small bowel) occurs in the first or second decade with rectal bleeding and anaemia. --- Explanation: This review directly supports frequent GI bleeding in the common form of JPS.

[PMID:36809082] [SUPPORT] JPS is caused by germline mutations in the SMAD4 or BMPR1A genes and is characterized by hamartomatous polyps in the gastrointestinal tract. --- Explanation: This case-based abstract confirms syndrome-level GI hamartomatous polyp disease in a patient presenting with clinically significant gastrointestinal bleeding.


MONDO:0017380

[PMID:7881943] [SUPPORT] The more common form of juvenile polyposis (affecting the colon, stomach and small bowel) occurs in the first or second decade with rectal bleeding and anaemia. --- Explanation: This directly supports anemia as a common clinical consequence of JPS-associated polyp bleeding.

[PMID:36809082] [SUPPORT] A 27-year-old female presented at 13 weeks' gestation with epigastric pain and anemia requiring blood and iron transfusions but no family history of gastrointestinal malignancy. --- Explanation: This case report provides direct human evidence that JPS can present with clinically significant anemia.


MONDO:0017380

[PMID:7881943] [SUPPORT] The rarer and often fatal form, namely, juvenile polyposis of infancy, is typified by diarrhoea, protein-losing enteropathy, bleeding and rectal prolapse. --- Explanation: This review directly supports diarrhea as a subtype-specific manifestation of juvenile polyposis of infancy within the JPS spectrum.


MONDO:0017380

[PMID:7881943] [SUPPORT] The rarer and often fatal form, namely, juvenile polyposis of infancy, is typified by diarrhoea, protein-losing enteropathy, bleeding and rectal prolapse. --- Explanation: This review directly supports protein-losing enteropathy as a subtype-specific manifestation of juvenile polyposis of infancy.


MONDO:0017380

[PMID:7881943] [SUPPORT] The rarer and often fatal form, namely, juvenile polyposis of infancy, is typified by diarrhoea, protein-losing enteropathy, bleeding and rectal prolapse. --- Explanation: This review directly supports rectal prolapse as a subtype-specific manifestation of juvenile polyposis of infancy.


MONDO:0017380

[PMID:35988962] [SUPPORT] Among the syndromic features, JPS can present with concomitant extra-intestinal manifestations, above all cutaneous manifestations such as telangiectasia, pigmented nevi, and skeletal stigmata. --- Explanation: This overview supports telangiectasia as an occasional extra-intestinal manifestation within the JPS spectrum.


MONDO:0017380

[PMID:35988962] [SUPPORT] In JPS a cumulative risk of CRC of 39-68% has been estimated. --- Explanation: This overview directly supports frequent colorectal cancer risk within the JPS spectrum.

[PMID:7881943] [SUPPORT] Epithelial dysplasia is common and the cumulative risk of colorectal cancer is > 50 per cent. --- Explanation: This review supports colorectal cancer as a major malignant outcome of JPS.


MONDO:0017380

[PMID:41199529] [SUPPORT] Both Ménétrier's disease (MD) and juvenile polyposis syndrome (JPS) are rare premalignant conditions that can lead to gastric cancer. --- Explanation: This directly supports stomach cancer as a specific malignant outcome associated with JPS.


MONDO:0017380

[PMID:35988962] [INDIRECT EVIDENCE] [SUPPORT] Pathogenic germline variants of either BMPR1A or SMAD4 cause the syndrome. --- Explanation: This overview identifies BMPR1A as a core causative gene in JPS.


MONDO:0017380

[PMID:35988962] [INDIRECT EVIDENCE] [SUPPORT] Pathogenic germline variants of either BMPR1A or SMAD4 cause the syndrome. --- Explanation: This overview identifies SMAD4 as a core causative JPS gene.


MONDO:0017380

[PMID:33822054] [INDIRECT EVIDENCE] [SUPPORT] Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. --- Explanation: This supports PTEN-BMPR1A contiguous deletion as the initiating lesion for the severe infantile subtype of JPS.


MONDO:0017380

[PMID:33822054] [INDIRECT EVIDENCE] [SUPPORT] Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. --- Explanation: The abstract supports PI3K-AKT-mTOR pathway hyperactivation as a therapeutically actionable disease mechanism in juvenile polyposis of infancy.


MONDO:0017380


MONDO:0017380

[PMID:22171123] [INDIRECT EVIDENCE] [SUPPORT] Both genes play a role in the BMP/TGF-beta signalling pathway. --- Explanation: This supports BMP/TGF-beta dysregulation as a central shared mechanism in BMPR1A- and SMAD4-mediated JPS.


MONDO:0017380

[PMID:22171123] [INDIRECT EVIDENCE] [SUPPORT] It has been suggested that cancer in juvenile polyposis may develop through the so-called "landscaper mechanism" where an abnormal stromal environment leads to neoplastic transformation of the adjacent epithelium and in the end invasive carcinoma. --- Explanation: This review supports the landscaper mechanism as a distinct stromal-epithelial pathophysiology in JPS.


MONDO:0017380

[PMID:33822054] [INDIRECT EVIDENCE] [SUPPORT] Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. --- Explanation: This supports a distinct severe infantile enteropathic and pan-enteric polyposis mechanism within the JPS spectrum.


MONDO:0017380

[PMID:7881943] [INDIRECT EVIDENCE] [SUPPORT] Juvenile polyposis is an uncommon condition characterized by the development of multiple juvenile polyps, predominantly in the colon but also in the rest of the gastrointestinal tract. --- Explanation: This supports hamartomatous juvenile polyp formation as a core pathophysiologic lesion of JPS.


MONDO:0017380

[PMID:7881943] [INDIRECT EVIDENCE] [SUPPORT] Epithelial dysplasia is common and the cumulative risk of colorectal cancer is > 50 per cent. --- Explanation: This supports dysplasia-associated neoplastic progression as a distinct late mechanism in JPS.


MAXO:0000130

[PMID:35988962] [SUPPORT] The oncological risk justifies and imposes prevention strategies that aim at the cancer risk reduction through endoscopic screening, as recommended by international scientific societies. --- Explanation: This overview supports endoscopic surveillance as the central preventive management strategy in JPS.

[PMID:7881943] [SUPPORT] Most patients are treated surgically for colonic polyps, although endoscopic polypectomy is also an option. --- Explanation: This supports endoscopic polypectomy as an established therapeutic option in JPS management.


MAXO:0000004

[PMID:7881943] [SUPPORT] Most patients are treated surgically for colonic polyps, although endoscopic polypectomy is also an option. --- Explanation: This review supports surgery as a common management approach for JPS colonic polyp burden.

[PMID:36809082] [SUPPORT] Total gastrectomy was performed at seven weeks post-partum. --- Explanation: This case report provides direct human evidence that severe gastric JPS can require definitive surgical resection.


MAXO:0000058

[PMID:33822054] [SUPPORT] Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07-0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). --- Explanation: This multicenter cohort supports pathway-specific mTOR inhibitor therapy for the severe PTEN-BMPR1A deletion subtype.


MAXO:0000079

[PMID:36359527] [SUPPORT] In JPS, a timely genetic diagnosis allows clinicians to better manage patients and to provide early surveillance and intervention for their asymptomatic mutated relatives in the early decades of life. --- Explanation: This supports genetic counseling and cascade surveillance as core management actions for familial JPS.


hgnc:1076

[PMID:35988962] [SUPPORT] Pathogenic germline variants of either BMPR1A or SMAD4 cause the syndrome. --- Explanation: This overview directly supports BMPR1A as a causative gene in JPS.


hgnc:6770

[PMID:35988962] [SUPPORT] Pathogenic germline variants of either BMPR1A or SMAD4 cause the syndrome. --- Explanation: This overview directly supports SMAD4 as a causative JPS gene.


hgnc:9588

[PMID:33822054] [SUPPORT] Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). --- Explanation: This supports PTEN as a subtype-specific contiguous deletion partner in juvenile polyposis of infancy.


MONDO:0017380

[PMID:35988962] [SUPPORT] The inheritance pattern is autosomal dominant. --- Explanation: This overview directly supports autosomal dominant inheritance for JPS.

[DOI:10.1093/gastro/goac082] [SUPPORT] Diseases in BMPR1A germline mutation carriers vary from mixed polyposis to sole colorectal cancer, and typical juvenile polyps do not always occur in these carriers. --- Explanation: This BMPR1A carrier series supports variable expressivity across the juvenile polyposis spectrum.


MONDO:0017380

[PMID:7881943] [SUPPORT] Epithelial dysplasia is common and the cumulative risk of colorectal cancer is > 50 per cent. --- Explanation: This review directly supports epithelial dysplasia as an important histopathologic feature of JPS polyps.


MONDO:0003865


MONDO:0003865

[PMID:41042158] [INDIRECT EVIDENCE] [PARTIAL] Mutation of c-KIT has been observed in acral, mucosal, and chronically sun-damaged melanoma subtypes marking it as a key therapeutic target for melanoma. --- Explanation: This abstract documents c-KIT mutations in melanoma subtypes associated with KIT-mutant disease.


MAXO:0000058

[PMID:23775962] [SUPPORT] Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. --- Explanation: Phase II trial reports response rates to imatinib in KIT-altered melanoma.


CHEBI:45783

[PMID:23775962] [INDIRECT EVIDENCE] [SUPPORT] Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. --- Explanation: Phase II trial reports response rates to imatinib in KIT-altered melanoma.


MAXO:0000058


CHEBI:52172


CHEBI:49375


HGNC.SYMBOL:KIT Exon 11 Mutations


HGNC.SYMBOL:KIT Exon 13 Mutations (K642E)


HGNC.SYMBOL:KIT Exon 17 Mutations (D820Y)


HGNC.SYMBOL:KIT Amplification


MONDO:0003865

[PMID:27268913] [PARTIAL] Malignant melanoma represents a neoplasm stemming from melanocytes --- Explanation: Abstract defines melanoma as a neoplasm stemming from melanocytes.


MONDO:0005061


MONDO:0005061

[PMID:33618059] [INDIRECT EVIDENCE] [PARTIAL] The KRAS glycine-to-cysteine mutation (G12C) composes approximately 44% of KRAS mutations in non-small cell lung cancer, with mutant KRasG12C present in approximately 13% of all patients with lung adenocarcinoma. --- Explanation: This abstract explicitly describes the KRAS G12C substitution and its frequency in NSCLC, supporting the oncogenic mutation context.


MAXO:0000058

[PMID:34096690] [SUPPORT] An objective response was observed in 46 patients (37.1% --- Explanation: Phase 2 trial reports objective responses to sotorasib in KRAS G12C NSCLC.


CHEBI:178199

[PMID:34096690] [INDIRECT EVIDENCE] [SUPPORT] An objective response was observed in 46 patients (37.1% --- Explanation: Phase 2 trial reports objective responses to sotorasib in KRAS G12C NSCLC.


MAXO:0000058

[PMID:35658005] [SUPPORT] Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response. --- Explanation: KRYSTAL-1 abstract reports objective responses to adagrasib in KRAS G12C NSCLC.


NCIT:C157493

[PMID:35658005] [INDIRECT EVIDENCE] [SUPPORT] Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response. --- Explanation: KRYSTAL-1 abstract reports objective responses to adagrasib in KRAS G12C NSCLC.


MAXO:0000647


HGNC.SYMBOL:KRAS


HGNC.SYMBOL:STK11


HGNC.SYMBOL:KEAP1


MONDO:0005061

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


MONDO:0007239

[PMID:15663649] [SUPPORT] This inherited keratinization disorder is characterized clinically by erythema, blistering, and peeling shortly after birth. --- Explanation: Confirms congenital erythroderma as a cardinal feature.


MONDO:0007239

[PMID:31335043] [SUPPORT] The condition was originally termed "bullous congenital ichthyosiform erythroderma" owing to the hallmark features of erythroderma, blistering, and skin denudation present at birth, with subsequent development of marked hyperkeratosis. --- Explanation: Confirms blistering as a hallmark neonatal feature.


MONDO:0007239

[PMID:15663649] [SUPPORT] It may resolve and be replaced with thick scaling. --- Explanation: Describes the transition from blistering to hyperkeratosis.


MONDO:0007239

[PMID:21271994] [SUPPORT] Epidermolytic ichthyosis (EI) is a hereditary keratinization disorder caused by mutations in the keratin 1 (KRT1) or keratin 10 (KRT10) genes. --- Explanation: Confirms ichthyosis as the defining clinical feature.


MONDO:0007239

[PMID:21271994] [SUPPORT] The presence of palmoplantar keratoderma suggests KRT1 mutations, whereas KRT10 mutations in most instances give rise to the nonpalmoplantar variants. --- Explanation: Confirms that PPK is characteristic of KRT1 mutations specifically.

[PMID:30288772] [SUPPORT] Epidermolytic ichthyosis (EI), the major keratinopathic ichthyosis, is characterized by congenital erythroderma, blistering and erosions of the skin. Causative mutations in KRT1 and KRT10 have been described, with PPK being present primarily in association with the former. --- Explanation: Directly links PPK to KRT1 mutations.


MONDO:0007239

[PMID:10053007] [SUPPORT] Three affected individuals exhibit dramatic episodic flares of annular, polycyclic erythematous plaques with scale, which coalesce to involve most of the body surface. The flares last weeks to months. --- Explanation: Describes the hallmark cyclic flaring pattern of annular EI.


MONDO:0007239

[PMID:10053007] [SUPPORT] Manifesting erythema and superficial erosions at birth, which improved during the first few months of life --- Explanation: Confirms superficial erosions as a neonatal feature.


MONDO:0007239

[PMID:21271994] [INDIRECT EVIDENCE] [SUPPORT] In most cases of severe EI, heterozygous single point mutations are found at the highly conserved helix boundary motifs of KRT1 and KRT10 that play a critical role in filament formation. --- Explanation: Confirms that heterozygous mutations at filament-critical helix boundary motifs disrupt keratin assembly.

[PMID:30288772] [INDIRECT EVIDENCE] [SUPPORT] Mutations in KRT1 are not only scattered throughout the keratin 1 protein, as opposed to being clustered, but can result in a range of phenotypes as further confirmed by these mutations, giving a complex genotype/phenotype pattern. --- Explanation: Demonstrates that KRT1 mutations throughout the protein lead to a spectrum of phenotypes.


MONDO:0007239


MONDO:0007239

[PMID:10053007] [INDIRECT EVIDENCE] [SUPPORT] Abnormal keratin-filament aggregates were observed in suprabasal keratinocytes from both probands, suggesting that the causative mutation might reside in keratin K1 or keratin K10. --- Explanation: Directly demonstrates keratin filament aggregation in suprabasal keratinocytes from affected individuals.

[PMID:31335043] [INDIRECT EVIDENCE] [SUPPORT] The condition was originally termed "bullous congenital ichthyosiform erythroderma" owing to the hallmark features of erythroderma, blistering, and skin denudation present at birth, with subsequent development of marked hyperkeratosis. --- Explanation: Confirms the hallmark blistering and hyperkeratosis phenotype resulting from keratinocyte cytolysis.


MONDO:0007239

[PMID:29689068] [INDIRECT EVIDENCE] [SUPPORT] Our results highlight the importance and complexity of the KRT1/10 V2 domain in keratin dimer formation and the potential consequences of its alteration. --- Explanation: Demonstrates that V2 domain mutations alter keratin dimer formation, contributing to compensatory hyperkeratosis in the Curth-Macklin variant.


MAXO:0000058

[PMID:15663649] [SUPPORT] We review this disorder and its therapy, which is mainly symptomatic with emollients and retinoids. --- Explanation: Confirms emollients as primary symptomatic therapy.


MAXO:0000058

[PMID:15663649] [SUPPORT] We review this disorder and its therapy, which is mainly symptomatic with emollients and retinoids. --- Explanation: Confirms retinoids as part of the therapeutic approach.


hgnc:6412

[PMID:15663649] [SUPPORT] Genetically, this is an autosomal dominant disease with complete penetrance; however, 50% are spontaneous mutations. The clinical phenotype is a result of alterations in the gene(s) for keratin 1 and/or 10. --- Explanation: Confirms AD inheritance, complete penetrance, and 50% de novo rate for KRT1/10 mutations.

[PMID:30288772] [SUPPORT] Mutations in KRT1 are not only scattered throughout the keratin 1 protein, as opposed to being clustered, but can result in a range of phenotypes as further confirmed by these mutations, giving a complex genotype/phenotype pattern. --- Explanation: Confirms genotype-phenotype complexity with mutations scattered across the KRT1 gene.

[PMID:29689068] [SUPPORT] While IH-CM is associated with mutations in the keratin 1 (KRT1) gene, reports to date have indicated that mutations in the KRT1 gene result in an aberrant and truncated protein tail, essentially affecting the function of the V2 domain. --- Explanation: Confirms V2 tail domain mutations as the basis for Curth-Macklin type.


MONDO:0007239

[PMID:15663649] [SUPPORT] Genetically, this is an autosomal dominant disease with complete penetrance; however, 50% are spontaneous mutations. --- Explanation: Confirms autosomal dominant inheritance with complete penetrance and a high rate of de novo mutations.

[PMID:21271994] [SUPPORT] In most cases of severe EI, heterozygous single point mutations are found at the highly conserved helix boundary motifs of KRT1 and KRT10 that play a critical role in filament formation. --- Explanation: Heterozygous mutations confirm dominant mechanism.


MONDO:0016512

[PMID:30514738] [SUPPORT] Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. --- Explanation: Supports long palpebral fissures as a defining clinical feature.


MONDO:0016512

[PMID:30514738] [SUPPORT] Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. --- Explanation: Lists arched broad eyebrows as a primary diagnostic dysmorphic feature.


MONDO:0016512

[PMID:30514738] [SUPPORT] The authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined below) at some point of life. --- Explanation: Places intellectual disability in the core diagnostic phenotype.

[PMID:15523636] [SUPPORT] Based on these patients and a review of the literature, in the absence of major structural brain anomalies, the average intelligence quotient (IQ) in patients with this condition fall within the mild mental retardation range, however, specific developmental outcomes are widely variable, ranging from severe MR to normal intelligence. --- Explanation: Supports the typical severity range and variable developmental outcome.


MONDO:0016512

[PMID:21607748] [SUPPORT] Kabuki syndrome (KS) is one of the classical, clinically well-known multiple anomalies/mental retardation syndromes, mainly characterized by a very distinctive facial appearance in combination with additional clinical signs such as developmental delay, short stature, persistent fingerpads, and urogenital tract anomalies. --- Explanation: Supports short stature as a common core feature.


MONDO:0016512

[PMID:30514738] [SUPPORT] The authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined below) at some point of life. --- Explanation: Supports hypotonia as a core early-life phenotype.


MONDO:0016512

[PMID:28884922] [SUPPORT] In conclusion, a CHD is detected in 70% of patients with KMT2D (MLL2) pathogenic variants, most commonly left-sided obstructive lesions, including multiple left-sided obstructions similar to those observed in the spectrum of the Shone complex, and septal defects. --- Explanation: Supports congenital heart disease as a frequent and clinically important manifestation.


MONDO:0016512

[PMID:26194542] [SUPPORT] Among the patients with KMT2D mutations (KMT2D(Mut/+)), hypogammaglobulinemia was detected in all but 1 patient, with IgA deficiency affecting 90% of patients and a deficiency in at least 1 other isoform seen in 40% of patients. --- Explanation: Supports IgA deficiency as a prevalent immunologic phenotype.


MONDO:0016512

[PMID:31363182] [SUPPORT] Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; --- Explanation: Supports recurrent infection susceptibility in a large cohort.


MONDO:0016512

[PMID:30514738] [SUPPORT] Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. --- Explanation: Persistent fingertip pads are listed as one of the core diagnostic dysmorphic features.


MONDO:0016512

[PMID:11343317] [PARTIAL] Kabuki makeup (Niikawa-Kuroki) syndrome (KS) is characterized by distinct facial anomalies, mental retardation, congenital heart defect (CHD), and skeletal malformations. --- Explanation: Supports skeletal malformations broadly as a cardinal KS feature; scoliosis is a documented manifestation but not specifically named in this CHD-focused paper.


MONDO:0016512

[PMID:34570271] [SUPPORT] Kabuki syndrome (KS) is a genetic disorder caused mainly by de novo pathogenic variants in KMT2D or KDM6A, characterized by recognizable facial features, intellectual disability, and multi-systemic involvement, including short stature, microcephaly, hearing loss, cardiac defects, and additional congenital anomalies. --- Explanation: Identifies hearing loss as a recognized multisystem feature.

[PMID:15523636] [SUPPORT] The presence or absence of hearing loss or major malformations, other than those involving the brain, was not predictive of developmental outcome. --- Explanation: Acknowledges hearing loss as a feature while noting it does not predict cognitive outcome.


MONDO:0016512


MONDO:0016512

[PMID:34570271] [SUPPORT] CAKUT were detected in 8/13 (61.5%) of patients and varied from hypospadias, hydronephrosis, or double collecting systems to pelvic kidney, kidney asymmetry, horseshoe kidney, or kidney agenesis. --- Explanation: Demonstrates a high prevalence of CAKUT in a single-center cohort of KS patients.

[PMID:21607748] [SUPPORT] MLL2 mutation carriers significantly more often presented with short stature and renal anomalies (p = 0.026 and 0.031, respectively) --- Explanation: Renal anomalies are significantly associated with KMT2D mutation-positive patients.


MONDO:0016512

[PMID:24633898] [INDIRECT EVIDENCE] [SUPPORT] Kabuki syndrome (KS) is a multiple congenital anomalies syndrome characterized by characteristic facial features and varying degrees of mental retardation, caused by mutations in KMT2D/MLL2 and KDM6A/UTX genes. --- Explanation: Establishes the two principal disease genes and the syndrome's developmental basis.

[PMID:24633898] [INDIRECT EVIDENCE] [SUPPORT] We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. --- Explanation: Supports haploinsufficiency as a core molecular mechanism.

[PMID:22197486] [INDIRECT EVIDENCE] [SUPPORT] Here, we describe three KS individuals with de novo partial or complete deletions of an X chromosome gene, KDM6A, that encodes a histone demethylase that interacts with MLL2. --- Explanation: Connects KDM6A loss to the same chromatin-regulatory disease mechanism.


MONDO:0016512

[PMID:29073101] [INDIRECT EVIDENCE] [SUPPORT] We now establish Kabuki syndrome as a neurocristopathy, whereby the majority of clinical features are modeled in mice carrying neural crest (NC) deletion of UTX, including craniofacial dysmorphism, cardiac defects, and postnatal growth retardation. --- Explanation: Supports neural crest dysfunction as a unifying developmental mechanism.

[PMID:31479440] [INDIRECT EVIDENCE] [SUPPORT] Our zebrafish Kabuki Syndrome model reveals a regulatory link between the Notch pathway and Kmt2d during endothelium and endocardium patterning and shows that pharmacological inhibition of Notch signaling rebalances Rbpj protein levels and rescues the cardiovascular phenotype by enhancing endothelial and endocardial cell proliferation and stabilizing endocardial patterning. --- Explanation: Supports a specific cardiovascular mechanism downstream of KMT2D deficiency.


MONDO:0016512

[PMID:26194542] [INDIRECT EVIDENCE] [SUPPORT] Among the patients with KMT2D mutations (KMT2D(Mut/+)), hypogammaglobulinemia was detected in all but 1 patient, with IgA deficiency affecting 90% of patients and a deficiency in at least 1 other isoform seen in 40% of patients. --- Explanation: Supports a high-burden humoral immunodeficiency phenotype in KMT2D-related disease.

[PMID:26194542] [INDIRECT EVIDENCE] [SUPPORT] Impaired terminal differentiation was noted in primary B cells from patients with KMT2D(Mut/+) mutations. --- Explanation: Supports a cell-intrinsic B-cell maturation defect.

[PMID:31363182] [INDIRECT EVIDENCE] [SUPPORT] Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; --- Explanation: Confirms that immune dysfunction and autoimmunity are common in a large registry cohort.


MONDO:0016512

[PMID:25273096] [INDIRECT EVIDENCE] [SUPPORT] In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell layer of Kmt2d(+/βGeo) mice correlated with reduced neurogenesis and hippocampal memory defects. --- Explanation: Supports a mechanistic link between KMT2D-dependent chromatin defects and cognitive impairment.


MAXO:0000058

[PMID:25273096] [SUPPORT] These abnormalities improved upon postnatal treatment with AR-42. Our work suggests that a reversible deficiency in postnatal neurogenesis underlies intellectual disability in Kabuki syndrome. --- Explanation: Demonstrates that HDAC inhibitor treatment can rescue neurogenesis and memory deficits in a Kabuki syndrome mouse model.


MAXO:0000780


MAXO:0000930

[PMID:15523636] [PARTIAL] Based on these patients and a review of the literature, in the absence of major structural brain anomalies, the average intelligence quotient (IQ) in patients with this condition fall within the mild mental retardation range, however, specific developmental outcomes are widely variable, ranging from severe MR to normal intelligence. --- Explanation: Supports significant developmental variability warranting early intervention; speech therapy specifically is not discussed in this paper.


MAXO:0025001

[PMID:11343317] [SUPPORT] CHD was diagnosed in 35 (58%) of our patients. Aortic coarctation (COA) (23%), atrial septal defect (ASD) (20%), and ventricular septal defect (VSD) (17%) were the most frequent CHDs --- Explanation: High frequency of congenital heart defects necessitates surgical evaluation and repair.


MAXO:0001480

[PMID:15887282] [PARTIAL] Due to this increased susceptibility to infection, children with KS should have immunologic evaluations at the time of diagnosis in order to reduce preventable morbidity and mortality. --- Explanation: Supports the clinical need for immunologic work-up but does not explicitly recommend immunoglobulin replacement therapy.


NCIT:C2701

[PMID:15887282] [INDIRECT EVIDENCE] [PARTIAL] Due to this increased susceptibility to infection, children with KS should have immunologic evaluations at the time of diagnosis in order to reduce preventable morbidity and mortality. --- Explanation: Supports the clinical need for immunologic work-up but does not explicitly recommend immunoglobulin replacement therapy.


hgnc:7133

[PMID:20711175] [SUPPORT] Our results strongly suggest that mutations in MLL2 are a major cause of Kabuki syndrome. --- Explanation: Establishes KMT2D as the major causative gene.

[PMID:24633898] [SUPPORT] We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. --- Explanation: Supports KMT2D haploinsufficiency as the dominant genetic mechanism.


hgnc:12637

[PMID:22197486] [SUPPORT] Here, we describe three KS individuals with de novo partial or complete deletions of an X chromosome gene, KDM6A, that encodes a histone demethylase that interacts with MLL2. --- Explanation: Establishes KDM6A as a causative Kabuki syndrome gene.


MONDO:0016512

[PMID:20711175] [SUPPORT] We demonstrate the successful application of exome sequencing to discover a gene for an autosomal dominant disorder, Kabuki syndrome (OMIM%147920). --- Explanation: Supports autosomal dominant inheritance for the common KMT2D-related form.


MONDO:0016512

[PMID:22197486] [SUPPORT] Here, we describe three KS individuals with de novo partial or complete deletions of an X chromosome gene, KDM6A, that encodes a histone demethylase that interacts with MLL2. --- Explanation: Supports an X-linked disease mechanism for the KDM6A-related form.


MONDO:0005055


MONDO:0005055

[PMID:7489408] [INDIRECT EVIDENCE] [SUPPORT] KSHV/HHV-8 is present in the flat endothelial cells lining vascular spaces of KS lesions as well as in typical KS spindle cells. --- Explanation: Abstract reports HHV-8 presence in endothelial and spindle cells in KS lesions.


MAXO:0000058


MAXO:0000647


CHEBI:28748


CHEBI:45863


MAXO:0000014


HGNC.SYMBOL:HHV-8 Viral Oncogenes


NCBITaxon:37296

[PMID:34731971] [SUPPORT] HHV8 is the etiological agent of Kaposi sarcoma, and of rare B cell lymphoproliferative disorders mostly observed in immunocompromised hosts (patients with AIDS, transplant organ recipients) such as primary effusion lymphoma and the plasma cell variant of multicentric Castleman disease. --- Explanation: Confirms HHV-8/KSHV as the etiologic agent of Kaposi sarcoma.


MONDO:0005055

[PMID:16188485] [SUPPORT] Spindle cells represent the main cell type of the advanced final nodular stage --- Explanation: Abstract notes spindle cells as the main cell type in advanced Kaposi sarcoma lesions.


MONDO:0012727

[PMID:30029859] [SUPPORT] Fever, abdominal pain, and vomiting were the most frequent symptoms observed and typical Kawasaki disease signs and symptoms appeared after intestinal complaints in all cases. --- Explanation: The literature mentions fever as one of the most frequent symptoms observed in Kawasaki disease, supporting the statement that fever is a very frequent systemic diagnostic symptom of Kawasaki disease.

[PMID:31900257] [SUPPORT] The conundrum for acute paediatricians is which clinical features best distinguish the febrile child with possible KD, needing intravenous immunoglobulin, from the many other children with febrile illnesses. --- Explanation: The literature highlights the challenge of distinguishing Kawasaki disease from other febrile illnesses, indicating that fever is a very frequent systemic diagnostic symptom in Kawasaki disease.

[PMID:26631821] [SUPPORT] The main symptoms were fever (100%), exanthema (98%), changes in the extremities (91%), conjunctivitis (77%), oral cavity changes (89%), cervical adenitis (55%) and cardiac abnormalities (45%). --- Explanation: The literature states that fever is present in 100% of the cases, supporting the statement that fever is a very frequent systemic diagnostic symptom of Kawasaki disease.


MONDO:0012727

[PMID:26631821] [SUPPORT] The main symptoms were fever (100%), exanthema (98%)... --- Explanation: Exanthema, which refers to a widespread rash, was present in 98% of the adult patients with Kawasaki Disease.

[PMID:1440951] [SUPPORT] We describe a four-year-old girl who presented with fever, a diffuse erythematous maculopapular rash... --- Explanation: The case description includes a diffuse erythematous maculopapular rash as one of the clinical features.

[PMID:33453126] [SUPPORT] All children with KD have fever accompanied by clinical signs, with four of the five classic criteria for complete KD being mucocutaneous... --- Explanation: The abstract emphasizes the mucocutaneous manifestations, which include skin rashes, as critical for diagnosing Kawasaki Disease.

[PMID:23481152] [SUPPORT] This is a report of a 4-year-old Hispanic boy who presented with skin changes to the lips and oral cavity, a generalized rash... --- Explanation: The case report mentions a generalized rash as one of the symptoms of Kawasaki Disease.

[PMID:32843441] [SUPPORT] Both patients presented with fever lasting >5 days and were found to have rash, conjunctival injection, and swollen lips. --- Explanation: The patients with COVID-19 inflammatory syndrome had clinical features resembling Kawasaki Disease, including a rash.


MONDO:0012727

[PMID:34814144] [SUPPORT] In cross-sectional studies, KD was associated with allergic rhinitis (n = 6; OR, 1.69; 95% CI, 1.52-1.87), asthma (n = 3; OR, 1.72; 95% CI, 1.38-2.14), allergic conjunctivitis (n = 2; OR, 1.95; 95% CI, 1.68-2.27), and atopic dermatitis (n = 3; OR, 1.35; 95% CI, 1.22-1.49). --- Explanation: The study shows that Kawasaki Disease is associated with allergic conjunctivitis, supporting the statement that conjunctivitis is very frequent in Kawasaki Disease.

[PMID:32843441] [SUPPORT] Both patients presented with fever lasting >5 days and were found to have rash, conjunctival injection, and swollen lips. --- Explanation: The description of conjunctival injection in patients with Kawasaki Disease supports the statement.

[PMID:7299613] [SUPPORT] In a prospective series, ophthalmologic examinations on 10 children with Kawasaki disease showed that eight had anterior uveitis during the acute phase of the illness. --- Explanation: Although the study focuses on anterior uveitis, it indicates significant ocular involvement in Kawasaki Disease, supporting the statement indirectly.


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[PMID:33527178] [SUPPORT] In Kawasaki disease (KD), thrombocytosis is commonly found in the subacute phase. --- Explanation: Thrombocytosis is a common finding during the subacute phase of KD.

[PMID:6833960] [SUPPORT] The second, subacute, phase begins with a decline of the acute findings and proceeds with desquamation of rash, joint manifestations, thrombocytosis, and cardiac disease. --- Explanation: Thrombocytosis occurs during the subacute phase of KD.


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[PMID:31599798] [SUPPORT] Kawasaki disease is a childhood vasculitis of unknown origin, whose major complication is the development of coronary artery aneurysms (CAA). --- Explanation: This reference directly states that coronary artery aneurysm development is a major complication of Kawasaki disease.

[PMID:21447126] [SUPPORT] Histologically, coronary arteritis begins 6-8 days after the onset of KD, and leads immediately to inflammation of all layers of the artery. The inflammation spreads completely around the artery; as a result, structural components of the artery undergo intense damage; the artery then begins to dilate. --- Explanation: This reference describes the mechanism by which arterial inflammation leads to dilation and aneurysm formation in Kawasaki disease.


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[PMID:23188196] [INDIRECT EVIDENCE] [SUPPORT] Kawasaki disease (KD) is considered to be a kind of systemic vasculitis syndrome. It most frequently affects infants and young children and primarily invades medium-sized muscular arteries, including the coronary arteries. --- Explanation: The literature confirms that Kawasaki disease involves widespread inflammation of medium-sized arteries, including coronary arteries.

[PMID:31599798] [INDIRECT EVIDENCE] [SUPPORT] Kawasaki disease is a childhood vasculitis of unknown origin, whose major complication is the development of coronary artery aneurysms (CAA). --- Explanation: The literature supports that Kawasaki disease leads to vascular inflammation and aneurysm formation.

[PMID:27090101] [INDIRECT EVIDENCE] [SUPPORT] Coronary angiography showed multiple aneurysms which suggested sequelae of misdiagnosed Kawasaki disease. --- Explanation: The case report indicates that Kawasaki disease can lead to aneurysm formation as a result of vascular inflammation.

[PMID:36102118] [INDIRECT EVIDENCE] [SUPPORT] Long-term physiological dysfunction in coronary/systemic vasculature may persist in individuals with Kawasaki disease even in the absence of coronary artery abnormalities. --- Explanation: The literature suggests long-term vascular dysfunction due to Kawasaki disease, supporting the idea of widespread vascular inflammation.

[PMID:35420684] [INDIRECT EVIDENCE] [SUPPORT] Kawasaki disease, an acute febrile illness, can cause vasculitis in the coronary arteries. --- Explanation: The literature confirms that Kawasaki disease causes inflammation in coronary arteries, leading to complications such as aneurysms.

[PMID:16990356] [INDIRECT EVIDENCE] [SUPPORT] Kawasaki disease is an acute inflammatory syndrome that takes the form of systemic vasculitis, and predominantly affects children. Important complications of this disease are coronary artery dilation and aneurysm formation. --- Explanation: The literature supports the statement that Kawasaki disease involves widespread vascular inflammation and aneurysm formation.