MAXO:0000058

[PMID:29191819] [PARTIAL] Although the primary endpoint was not met, the results suggest favour for tocilizumab over placebo for time to relapse of TAK without new safety concerns. Further investigation is warranted to confirm the efficacy of tocilizumab in patients with refractory TAK. --- Explanation: The TAKT trial showed a trend favoring tocilizumab but did not meet its primary endpoint, providing partial support for efficacy.


MAXO:0000004


MONDO:0010098

[PMID:18363703] [SUPPORT] An enlarged pulp chamber, apical displacement of the pulpal floor, and no constriction at the level of the cementoenamel junction are the characteristic features. --- Explanation: Provides defining morphological features of taurodontia.


MONDO:0010098

[PMID:34897365] [SUPPORT] Taurodontism is a continuous anatomical variation of permanent and primary posterior teeth represented by an enlargement of the pulp cavity. --- Explanation: Directly supports enlarged pulp cavity as a core phenotype.


MONDO:0010098

[PMID:31914354] [SUPPORT] Wnt10a knockout in the whole tissue (EIIa-Cre;Wnt10aflox/flox) and in dental epithelium (K14-Cre;Wnt10aflox/flox) led to an absence of or apically located root furcation in molars of mice, a phenotype that resembled taurodontism. --- Explanation: Supports altered root furcation architecture as a central morphology.


MONDO:0010098

[DOI:10.3390/ijms25105179] [SUPPORT] Clinical findings of the patients included taurodontism, unseparated roots, long roots, tooth agenesis, a supernumerary tooth, torus palatinus, and torus mandibularis. --- Explanation: Human family data supports tooth agenesis as a co-occurring phenotype in some taurodontism-associated genotypes.


MONDO:0010098

[DOI:10.3390/ijms25105179] [SUPPORT] Clinical findings of the patients included taurodontism, unseparated roots, long roots, tooth agenesis, a supernumerary tooth, torus palatinus, and torus mandibularis. --- Explanation: Human family data supports supernumerary tooth as a co-occurring phenotype.


MONDO:0010098

[PMID:18363703] [INDIRECT EVIDENCE] [SUPPORT] Taurodontism can be defined as a change in tooth shape caused by the failure of Hertwig's epithelial sheath diaphragm to invaginate at the proper horizontal level. --- Explanation: Directly supports the canonical mechanism involving altered Hertwig sheath invagination.


MONDO:0010098


MONDO:0010098

[PMID:31914354] [INDIRECT EVIDENCE] [SUPPORT] our study provides the first in vivo evidence that epithelial Wnt10a guides root furcation formation and plays a crucial role in controlling the organized proliferation of adjacent mesenchymal cells by regulating proper Wnt4 expression during root furcation morphogenesis. --- Explanation: Supports a specific epithelial WNT10A mechanism in root furcation morphogenesis.


MONDO:0010098

[PMID:25629078] [INDIRECT EVIDENCE] [SUPPORT] WNT10A heterozygotes exhibited molar root taurodontism and mild tooth agenesis (with incomplete penetrance) in their permanent dentitions. --- Explanation: Supports human genotype-phenotype association between WNT10A variation and taurodontism.

[PMID:25629078] [INDIRECT EVIDENCE] [SUPPORT] We conclude that molar crown and root dysmorphologies are caused by WNT10A defects and that the severity of the tooth agenesis correlates with the number of defective WNT10A alleles. --- Explanation: Supports causative role of WNT10A defects in root dysmorphology including taurodontism.


MONDO:0010098

[DOI:10.1242/dev.202899] [INDIRECT EVIDENCE] [SUPPORT] Further studies reveal that Axin1 in the HERS negatively regulates the AKT1-mTORC1 pathway through binding to AKT1, leading to inhibition of ribosomal biogenesis and mRNA translation. --- Explanation: Establishes the upstream molecular mechanism in HERS.

[DOI:10.1242/dev.202899] [INDIRECT EVIDENCE] [SUPPORT] Sonic hedgehog (Shh) protein, a morphogen essential for root development, is over-synthesized by upregulated mTORC1 activity upon Axin1 inactivation. --- Explanation: Links translational dysregulation to altered Shh morphogen output.


MONDO:0010098

[DOI:10.3390/ijms25105179] [INDIRECT EVIDENCE] [SUPPORT] The variants segregated with the dental anomalies in all nine patients from the two families. --- Explanation: Supports genetic segregation of KCTD1 variants with dental anomaly phenotypes including taurodontism.

[DOI:10.3390/ijms25105179] [INDIRECT EVIDENCE] [SUPPORT] Functional studies on the p.Arg241Gln variant are consistent with an impact on β-catenin levels and canonical WNT signaling. --- Explanation: Supports mechanistic perturbation of WNT pathway signaling downstream of KCTD1 variation.


MAXO:0000004

[PMID:12775010] [SUPPORT] Endodontic treatment of a taurodont tooth is challenging, because it requires special care in handling and identifying the number of root canals. --- Explanation: Supports the need for tailored endodontic procedural planning.

[PMID:18363703] [SUPPORT] In performing root canal treatment on such teeth, one should appreciate the complexity of the root canal system, canal obliteration and configuration, and the potential for additional root canal systems. --- Explanation: Supports specific technical considerations for treatment in taurodont teeth.


hgnc:13829

[PMID:25629078] [SUPPORT] WNT10A heterozygotes exhibited molar root taurodontism and mild tooth agenesis (with incomplete penetrance) in their permanent dentitions. --- Explanation: Supports association of WNT10A variation with taurodontism phenotype in humans.


hgnc:2916

[PMID:15666299] [SUPPORT] Amelogenesis imperfecta hypoplastic-hypomaturation with taurodontism (AIHHT) is an autosomal dominant (AD) trait associated with enamel defects and enlarged pulp chambers. --- Explanation: Supports DLX3-linked syndromic context for taurodontism.


hgnc:18249

[DOI:10.3390/ijms25105179] [SUPPORT] Whole exome sequencing identified two unrelated families with rare (p.Arg241Gln) or novel (p.Pro243Ser) variants in KCTD1. --- Explanation: Provides direct human genetic association evidence for KCTD1 in taurodontism-associated phenotypes.


hgnc:903

[DOI:10.1242/dev.202899] [SUPPORT] Here, we show that Axin1, a scaffold protein that negatively regulates canonical Wnt signaling, is strongly expressed in the HERS. --- Explanation: Supports AXIN1 involvement in the key epithelial compartment for root morphogenesis.

[DOI:10.1242/dev.202899] [SUPPORT] Axin1 ablation in the HERS of mice leads to defective root development, but in a manner independent of canonical Wnt signaling. --- Explanation: Demonstrates mechanistic dependency of root development on Axin1 in vivo.


MONDO:0010098

[PMID:15666299] [SUPPORT] Amelogenesis imperfecta hypoplastic-hypomaturation with taurodontism (AIHHT) is an autosomal dominant (AD) trait associated with enamel defects and enlarged pulp chambers. --- Explanation: Directly supports AD inheritance in a taurodontism-associated condition.


MONDO:0010100

[PMID:25143775] [SUPPORT] All of them had a developmental disorder as a chief complaint. 38%of patients had a history of developmental delay or regression --- Explanation: Case series confirms developmental regression as a key presenting feature in GM2 gangliosidosis patients.

[PMID:22025593] [SUPPORT] Common symptoms at onset were developmental arrest (83%), startling (65%), and hypotonia (60%). --- Explanation: Natural history study of 97 patients confirms developmental arrest in 83% of infantile GM2 gangliosidosis cases.

[PMID:29618308] [SUPPORT] Inherited as a classical autosomal recessive disorder, this global disease of the nervous system induces developmental arrest with regression of attained milestones; neurodegeneration progresses rapidly to cause premature death in young children. --- Explanation: Review describes developmental arrest with regression of milestones as a core feature of Tay-Sachs disease.


MONDO:0010100

[PMID:19820796] [SUPPORT] The accumulation of lipid in retinal ganglion cells that leads to a chalk-white appearance of the fundus called 'cherry red spot' is the hallmark of Tay-Sachs disease. --- Explanation: Case report describes cherry-red spot as the hallmark ophthalmologic finding in Tay-Sachs disease.


MONDO:0010100

[PMID:22025593] [SUPPORT] Common symptoms at onset were developmental arrest (83%), startling (65%), and hypotonia (60%). --- Explanation: Natural history study of 97 patients confirms exaggerated startle response (startling) in 65% of infantile GM2 gangliosidosis patients.

[PMID:24534057] [SUPPORT] The augmented startle reflex appeared between the age of 3 and 17 months and disappeared between the age of 4 and 6 years. --- Explanation: Electrophysiological study documents the temporal evolution of the augmented startle reflex in Tay-Sachs disease.


MONDO:0010100

[PMID:22025593] [SUPPORT] Common symptoms at onset were developmental arrest (83%), startling (65%), and hypotonia (60%). --- Explanation: Natural history study confirms hypotonia in 60% of infantile GM2 gangliosidosis patients at disease onset.


MONDO:0010100

[PMID:25143775] [SUPPORT] 38%of patients had a history of developmental delay or regression and 22% had seizures. --- Explanation: Case series documents seizures as a clinical manifestation in GM2 gangliosidosis patients.


MONDO:0010100

[PMID:7732608] [SUPPORT] Generalized hypotonia, macrocephaly, hyperacusis and a retinal cherry red spot appearance were present. --- Explanation: Case report documents macrocephaly in Tay-Sachs disease.


MONDO:0010100

[PMID:24011710] [SUPPORT] Disorders such as Tay-Sachs or Niemann-Pick disease are the most familiar examples of dysfunction in sphingolipid metabolism and are typically associated with neurodegeneration and ocular findings such as blindness. --- Explanation: Review establishes blindness as a characteristic ocular finding in sphingolipidoses including Tay-Sachs disease.


MONDO:0010100

[PMID:19820796] [INDIRECT EVIDENCE] [SUPPORT] Tay-Sachs disease is an autosomal recessive disorder of sphingolipid metabolism, caused by enzyme hexosaminidase A deficiency that leads to an accumulation of GM2 in neurocytes which results in progressive loss of neurological function. --- Explanation: Supports hexosaminidase A deficiency as a core defect in Tay-Sachs disease.


MONDO:0010100

[PMID:22025593] [INDIRECT EVIDENCE] [SUPPORT] G(M2) gangliosidoses are caused by an inherited deficiency of lysosomal β-hexosaminidase and result in ganglioside accumulation in the brain. --- Explanation: GM2 gangliosidosis (includes Tay-Sachs) shows ganglioside accumulation in brain.


MONDO:0010100

[PMID:29618308] [INDIRECT EVIDENCE] [SUPPORT] Inherited as a classical autosomal recessive disorder, this global disease of the nervous system induces developmental arrest with regression of attained milestones; neurodegeneration progresses rapidly to cause premature death in young children. --- Explanation: Review describes rapid neurodegeneration in infantile GM2 gangliosidosis, consistent with neuronal loss.


MONDO:0010100


MAXO:0000950

[PMID:27491214] [SUPPORT] Both are devastating diseases without cure or specific treatment however, with the use of supportive aggressive medical management, the lifespan and quality of life has been extended for both diseases. --- Explanation: Review confirms supportive care extends lifespan and quality of life in GM2 gangliosidoses including Tay-Sachs disease.


MAXO:0000079

[PMID:12108829] [SUPPORT] Carrier testing for Tay-Sachs disease should be offered to couples when at least one individual is of Ashkenazi Jewish (carrier frequency 1/30), Pennsylvania Dutch, Southern Louisiana Cajun, or Eastern Quebec French Canadian descent. --- Explanation: Review establishes carrier screening recommendations for high-risk populations including Ashkenazi Jews.


MAXO:0000058

[PMID:27491214] [SUPPORT] Treatment with FDA-approved glucose analogs to reduce the amount of ganglioside substrate is used as off-label treatments for some patients. --- Explanation: Review confirms substrate reduction therapy using glucose analogs is being used off-label in GM2 gangliosidoses.


MAXO:0001001

[PMID:35145305] [SUPPORT] This study provides early safety and proof-of-concept data in humans for treatment of patients with TSD by AAV gene therapy. --- Explanation: First-in-human AAV gene therapy trial demonstrates safety and proof-of-concept for Tay-Sachs disease treatment.


hgnc:4878


MONDO:0012735

[PMID:25420144] [SUPPORT] Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe. --- Explanation: The original TBS paper identifies intellectual disability as a core characteristic of the syndrome.

[PMID:33811134] [SUPPORT] Affected patients have severe intellectual disability (ID) with or without epilepsy --- Explanation: Study of seven patients with KCNH1 variants confirms severe intellectual disability as a consistent finding across the phenotypic spectrum.


MONDO:0012735

[PMID:27267311] [SUPPORT] Epilepsy was present in 7/9 patients. Both generalized and focal tonic-clonic seizures were observed. --- Explanation: Systematic study of epilepsy in KCNH1-related syndromes documents the high prevalence and variable seizure types.

[PMID:36285361] [SUPPORT] Variants in the KCNH1 cause a spectrum of epileptic disorders ranging from a benign form of genetic isolated epilepsy/FS to intractable form of epileptic encephalopathy. --- Explanation: Phenotypic expansion study confirms the broad spectrum of epileptic manifestations in KCNH1-related disorders.


MONDO:0012735

[PMID:20683999] [SUPPORT] Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect. --- Explanation: Clinical review of TBS patients confirms aplasia/hypoplasia of the thumbnail as a consistent finding across multiple unrelated patients.

[PMID:32956079] [SUPPORT] nails were absent on both great toes and thumb --- Explanation: Case report documenting absent thumbnail as part of the characteristic TBS presentation.


MONDO:0012735

[PMID:25420144] [SUPPORT] Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe. --- Explanation: The original TBS paper identifies nail aplasia/hypoplasia of the great toe as a defining feature of the syndrome.

[PMID:20683999] [SUPPORT] Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect. --- Explanation: Clinical review confirms aplasia/hypoplasia of the great toe nail as a consistent finding across TBS patients.


MONDO:0012735

[PMID:26264464] [SUPPORT] TMBTS is characterized by intellectual disability (ID), epilepsy, dysmorphic facial features, broad thumbs and great toes with absent/hypoplastic nails. --- Explanation: Clinical review identifies broad thumbs as a characteristic feature of Temple-Baraitser syndrome.

[PMID:18203178] [SUPPORT] Our case has the additional finding of broad thumbs. --- Explanation: Early case report confirming broad thumbs as part of the TBS phenotype.


MONDO:0012735

[PMID:20683999] [SUPPORT] Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect. --- Explanation: Documents broadening and elongation of the halluces as a consistent pattern in TBS.

[PMID:26264464] [SUPPORT] TMBTS is characterized by intellectual disability (ID), epilepsy, dysmorphic facial features, broad thumbs and great toes with absent/hypoplastic nails. --- Explanation: Confirms broad great toes as a characteristic feature in the clinical review of KCNH1-related syndromes.


MONDO:0012735

[PMID:26264464] [SUPPORT] KCNH1 mutation-positive individuals present with severe ID, neonatal hypotonia, hypertelorism, broad nasal tip, wide mouth, nail a/hypoplasia, a proximal implanted and long thumb and long great toes. --- Explanation: Clinical comparison of all published KCNH1 mutation-positive individuals identifies wide mouth as a consistent craniofacial feature.

[PMID:32956079] [SUPPORT] mild dysmorphic facial features with a wide open mouth, a thick vermilion border of the upper lip and downturned corners of the mouth --- Explanation: Case report documents wide mouth as part of TBS facial dysmorphism.


MONDO:0012735

[PMID:32956079] [SUPPORT] mild dysmorphic facial features with a wide open mouth, a thick vermilion border of the upper lip and downturned corners of the mouth --- Explanation: Case report documents thick vermilion border as part of the characteristic TBS facial features.

[PMID:25629734] [SUPPORT] everted and thick vermilion of both the upper and lower lips --- Explanation: Clinical description of TBS patients documents thick vermilion borders as a consistent craniofacial finding.


MONDO:0012735

[PMID:25629734] [SUPPORT] This study reports on two individuals with Temple-Baraitser syndrome, manifesting typical hallux and pollex findings, global developmental delay, and seizures. --- Explanation: Clinical study identifies global developmental delay as a consistent feature of TBS.

[PMID:40986435] [SUPPORT] these genetic disorders are now recognized as belonging to a broad spectrum of KCNH1-related encephalopathies characterized by developmental delay, intellectual disability, facial dysmorphism and infantile-onset seizures --- Explanation: Recent review confirms developmental delay as a core feature of KCNH1-related disorders.


MONDO:0012735

[PMID:26264464] [SUPPORT] KCNH1 mutation-positive individuals present with severe ID, neonatal hypotonia, hypertelorism, broad nasal tip, wide mouth, nail a/hypoplasia, a proximal implanted and long thumb and long great toes. --- Explanation: Clinical review identifies neonatal hypotonia as a common feature across KCNH1 mutation-positive individuals.

[PMID:25629734] [SUPPORT] There was generalized hypotonia. --- Explanation: Clinical description of TBS patient documents generalized hypotonia as a presenting feature.


MONDO:0012735

[PMID:27267311] [SUPPORT] EEG showed a diffusely slow background in 7/7 patients with epilepsy, with variable epileptiform abnormalities. --- Explanation: Systematic study of epilepsy in KCNH1-related syndromes documents EEG abnormalities as a universal finding in affected individuals with epilepsy.

[PMID:32956079] [SUPPORT] Electroencephalogram showed a diffusely slow background. --- Explanation: Case report confirms diffusely slow EEG background as a characteristic finding in TBS.


MONDO:0012735

[PMID:41656275] [INDIRECT EVIDENCE] [SUPPORT] coexpression with Kv10.1 or Kv10.2 shifted the half-maximum voltage of activation in the hyperpolarizing direction --- Explanation: Electrophysiology demonstrates that KCNH1 gain-of-function mutations shift activation voltage in the hyperpolarizing direction.

[PMID:38372889] [INDIRECT EVIDENCE] [SUPPORT] ZJUCHi003-derived neurons manifested slower action potential repolarization process and wider action potential half-width than the normal neurons. --- Explanation: Patient-derived iPSC neurons demonstrate altered electrophysiology consistent with KCNH1 gain-of-function.


MONDO:0012735


MONDO:0012735

[PMID:27267311] [INDIRECT EVIDENCE] [SUPPORT] Epilepsy is a key phenotypic feature in most individuals with KCNH1-related syndromes, suggesting a direct role of KCNH1 in epileptogenesis, although the underlying mechanism is not understood. --- Explanation: Clinical evidence supports a direct role of KCNH1 dysfunction in epileptogenesis through altered neuronal excitability.

[PMID:41656275] [INDIRECT EVIDENCE] [SUPPORT] Our findings imply that interpretation of clinical symptoms related to Kv10 GoF mutations requires considering the functional crosstalk with Kv10.1 and Kv10.2 subunits, which are both expressed in glutamatergic neurons in cortical Layers III and IV. --- Explanation: KCNH1 gain-of-function affects glutamatergic neurons in specific cortical layers, implicating excitatory network dysfunction.


MONDO:0012735

[PMID:40986435] [INDIRECT EVIDENCE] [SUPPORT] these genetic disorders are now recognized as belonging to a broad spectrum of KCNH1-related encephalopathies characterized by developmental delay, intellectual disability, facial dysmorphism and infantile-onset seizures --- Explanation: Review confirms that KCNH1 gain-of-function produces a spectrum of neurodevelopmental encephalopathies.

[PMID:33811134] [INDIRECT EVIDENCE] [SUPPORT] Affected patients have severe intellectual disability (ID) with or without epilepsy --- Explanation: Severe intellectual disability is a consistent finding even in patients without classical TBS features, indicating a core neurodevelopmental mechanism.


MONDO:0012735

[PMID:35639255] [INDIRECT EVIDENCE] [SUPPORT] the pathogenic missense variants (L352V and R330Q; NP_002229.1) perturb cilia morphology, assembly/disassembly, and Sonic Hedgehog signaling, disclosing a multifaceted role of the protein. --- Explanation: Direct experimental evidence that KCNH1 gain-of-function variants disrupt primary cilia biology and Hedgehog signaling.

[PMID:35639255] [INDIRECT EVIDENCE] [SUPPORT] KCNH1 localizes at the base of the cilium in pre-ciliary vesicles and ciliary pocket of human dermal fibroblasts and retinal pigment epithelial (hTERT RPE1) cells --- Explanation: Subcellular localization of KCNH1 at the cilium base establishes a direct structural link to ciliogenesis.


MAXO:0000058

[PMID:27267311] [SUPPORT] Complete seizure control was achieved with pharmacological treatment in 2/7 patients; polytherapy was required in 4/7 patients. --- Explanation: Systematic study documents the variable response to antiepileptic drug therapy in KCNH1-related epilepsy.

[PMID:40986435] [SUPPORT] We argue that allosteric modulators of Kv10.1 that induce a depolarizing shift in the channel's activation threshold are more likely to provide seizure control in KCNH1 epilepsy patients than pore blockers that annihilate channel function. --- Explanation: Recent review supports the theoretical basis for targeted channel modulation as a rational therapeutic strategy.


CHEBI:63631

[PMID:27267311] [INDIRECT EVIDENCE] [SUPPORT] Complete seizure control was achieved with pharmacological treatment in 2/7 patients; polytherapy was required in 4/7 patients. --- Explanation: Systematic study documents the variable response to antiepileptic drug therapy in KCNH1-related epilepsy.

[PMID:40986435] [INDIRECT EVIDENCE] [SUPPORT] We argue that allosteric modulators of Kv10.1 that induce a depolarizing shift in the channel's activation threshold are more likely to provide seizure control in KCNH1 epilepsy patients than pore blockers that annihilate channel function. --- Explanation: Recent review supports the theoretical basis for targeted channel modulation as a rational therapeutic strategy.


CHEBI:3387


MAXO:0000058


MAXO:0000011

[PMID:40604848] [SUPPORT] The first step of oral treatment consisted of myofunctional and speech/language therapy to stimulate biting and chewing. It also helped with the rehabilitation of proper tongue function. --- Explanation: Case report documents the use of myofunctional and speech/language therapy as part of a comprehensive treatment protocol for KCNH1-related syndrome.

[PMID:25629734] [SUPPORT] By 5 years of age she started using single words and was able to feed herself using utensils. --- Explanation: Natural history documentation shows that TBS patients can achieve developmental milestones over time, supporting the role of ongoing developmental therapies.


MAXO:0000011

[PMID:40604848] [INDIRECT EVIDENCE] [SUPPORT] The first step of oral treatment consisted of myofunctional and speech/language therapy to stimulate biting and chewing. It also helped with the rehabilitation of proper tongue function. --- Explanation: Case report documents the use of myofunctional and speech/language therapy as part of a comprehensive treatment protocol for KCNH1-related syndrome.

[PMID:25629734] [INDIRECT EVIDENCE] [SUPPORT] By 5 years of age she started using single words and was able to feed herself using utensils. --- Explanation: Natural history documentation shows that TBS patients can achieve developmental milestones over time, supporting the role of ongoing developmental therapies.


MAXO:0000011


MAXO:0000950

[PMID:25629734] [SUPPORT] At 9.5 years of age she had a vocabulary of ~40 words, followed a one-step command, walked up and down stairs, and rode a three-wheeled toy. --- Explanation: Detailed functional assessment of a TBS patient documents capacity for learning and skill acquisition over time, supporting the need for tailored educational interventions.

[PMID:37817707] [SUPPORT] caused pharma coresistantseizures and autistic behaviour in a 2.7-year-old boy --- Explanation: Report of autistic behavior in a patient with KCNH1 mutation highlights the need for behavioral support alongside educational interventions.


MAXO:0000950

[PMID:25629734] [INDIRECT EVIDENCE] [SUPPORT] At 9.5 years of age she had a vocabulary of ~40 words, followed a one-step command, walked up and down stairs, and rode a three-wheeled toy. --- Explanation: Detailed functional assessment of a TBS patient documents capacity for learning and skill acquisition over time, supporting the need for tailored educational interventions.

[PMID:37817707] [INDIRECT EVIDENCE] [SUPPORT] caused pharma coresistantseizures and autistic behaviour in a 2.7-year-old boy --- Explanation: Report of autistic behavior in a patient with KCNH1 mutation highlights the need for behavioral support alongside educational interventions.


MAXO:0000950


MAXO:0000079

[PMID:25420144] [SUPPORT] we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. --- Explanation: Discovery of maternal mosaicism with variable phenotypic expression highlights the critical importance of genetic counseling for recurrence risk assessment and parental testing.

[PMID:36285361] [SUPPORT] All hotspot variants associated with epileptic encephalopathy clustered in transmembrane domain (S4 and S6), while those with isolated epilepsy/seizures or TBS/ZLS without epilepsy were scattered in the KCNH1. --- Explanation: Genotype-phenotype correlations based on variant location provide important information for prognostic counseling of affected families.


HGNC.SYMBOL:KCNH1 pathogenic variants

[PMID:25420144] [SUPPORT] Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether à go-go, EAG1 or KV10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six individuals with TBS. --- Explanation: Establishes KCNH1 mutations as the genetic cause of Temple-Baraitser syndrome.


MONDO:0012735

[PMID:25420144] [SUPPORT] we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. --- Explanation: Demonstrates that most cases are de novo but maternal mosaicism can occur with milder phenotypes.


MONDO:0010279

[PMID:20598277] [SUPPORT] Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs --- Explanation: Confirms limb skeletal dysplasia as a defining feature.


MONDO:0010279

[PMID:20598277] [SUPPORT] pigmentary defects of the skin --- Explanation: Pigmentary skin defects are a defining feature of TOD.

[PMID:26059211] [SUPPORT] deformities of the hands and feet, craniofacial abnormalities, and discolored, linear facial lesions --- Explanation: Confirms the pigmentary skin defect phenotype.


MONDO:0010279

[PMID:20598277] [SUPPORT] recurrent digital fibroma with onset in female infancy --- Explanation: Recurrent digital fibromas are a defining feature of TOD.

[PMID:20598277] [SUPPORT] RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. --- Explanation: Demonstrates that the mutant FLNA allele escapes X-inactivation silencing specifically in fibroma tissue.


MONDO:0010279

[PMID:20598277] [INDIRECT EVIDENCE] [SUPPORT] The variant c.5217G>A was found in six unrelated cases (three families and three sporadic cases) --- Explanation: Identifies the single recurrent FLNA mutation causing TOD.

[PMID:20598277] [INDIRECT EVIDENCE] [SUPPORT] The variant activates a cryptic splice site, removing the last 48 nucleotides from exon 31. At the protein level, this results in a loss of 16 amino acids (p.Val1724_Thr1739del), predicted to remove a sequence at the surface of filamin repeat 15. --- Explanation: Defines the molecular mechanism of the TOD mutation.


MONDO:0010279


MONDO:0010279

[PMID:20598277] [INDIRECT EVIDENCE] [SUPPORT] RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. --- Explanation: Demonstrates tissue-specific expression of the mutant allele due to X-inactivation patterns.


MONDO:0010279

[PMID:26059211] [INDIRECT EVIDENCE] [SUPPORT] The finding of absent elastic fibers in the skin lesions suggests that mutated filamin A, in part, exerts its effects through dysregulated elastin biology --- Explanation: Proposes dysregulated elastin biology as a mechanism for connective tissue manifestations in FLNA disorders including TOD.


MAXO:0000004


MAXO:0000079


hgnc:3754

[PMID:20598277] [SUPPORT] Our data show that TOD is caused by this single recurrent mutation in the FLNA gene. --- Explanation: Confirms a single recurrent mutation as the cause of all TOD cases.

[PMID:26059211] [SUPPORT] Recent studies have identified a FLNA c.5217G>A mutation as the cause of TODPD, allowing for diagnostic genetic testing. --- Explanation: Confirms the specific mutation and its diagnostic utility.


MONDO:0010108

[PMID:37820296] [SUPPORT] Testicular GCTs (TGCTs) are the most common cancers in 15- to 39-year-old men --- Explanation: Confirms TGCTs are the most common cancers in young adult men.


MONDO:0010108


MONDO:0010108

[PMID:38541652] [INDIRECT EVIDENCE] [SUPPORT] the genetic and epigenetic factors involved in the pathogenesis of testicular germ cell tumors (TGCTs) --- Explanation: This review describes the developmental origin of TGCTs from PGCs through genetic and epigenetic alterations.

[PMID:38791003] [INDIRECT EVIDENCE] [SUPPORT] epigenetics has recently come into the spotlight as a major factor in TGCT initiation, progression, and even resistance to treatment --- Explanation: Supports epigenetic mechanisms underlying GCNIS formation and TGCT progression.


MONDO:0010108

[PMID:36835562] [INDIRECT EVIDENCE] [SUPPORT] Epigenetic mechanisms, such as methylations of cytosines on the DNA string and methylations and acetylations of histone 3 lysines, regulate expression of these driver genes between the TGCT subtypes --- Explanation: Supports the role of 12p-located driver genes (including NANOG) in TGCT tumorigenesis through epigenetic regulation.


MONDO:0010108

[PMID:38541652] [INDIRECT EVIDENCE] [SUPPORT] several genomic and transcriptomic assays have identified a few significantly mutated somatic genes, primarily KIT and K-RAS --- Explanation: Confirms KIT and K-RAS as the primary significantly mutated somatic genes in TGCTs.


MONDO:0010108

[PMID:37891379] [INDIRECT EVIDENCE] [SUPPORT] metastatic testicular germ cell tumors (TGCT) are cured in over 80% of patients using cisplatin-based combination therapy. Published data suggest that TGCTs are sensitive to cisplatin due to limited DNA repair and presumably also to a propensity to undergo apoptosis --- Explanation: Directly supports the dual mechanism of cisplatin sensitivity - limited DNA repair and strong apoptotic propensity in TGCTs.

[PMID:37891379] [INDIRECT EVIDENCE] [SUPPORT] both the death receptor and the mitochondrial apoptotic pathway become strongly activated in TTC following cisplatin treatment, explaining, together with attenuated DNA repair, their unique sensitivity toward platinum-based anticancer drugs --- Explanation: Confirms both death receptor and mitochondrial apoptotic pathways are activated in cisplatin-treated testis tumor cells.

[PMID:37175579] [INDIRECT EVIDENCE] [SUPPORT] Testicular germ-cell tumors (TGCT) have been widely recognized for their outstanding survival rates, commonly attributed to their high sensitivity to cisplatin-based therapies --- Explanation: Confirms the clinical observation of high cisplatin sensitivity and outstanding survival rates in TGCT.


MONDO:0010108

[PMID:38275869] [INDIRECT EVIDENCE] [SUPPORT] approximately 15% of the patients develop platinum-refractory disease and suffer multiple relapses --- Explanation: Confirms the ~15% rate of cisplatin resistance in TGCT patients.

[PMID:37024667] [INDIRECT EVIDENCE] [SUPPORT] We identified overactivation of neddylation as a factor for cisplatin resistance in TGCTs and highlighted the additive effect of NAE1 inhibition by MLN4924 in combination with cisplatin as a novel treatment option for TGCTs --- Explanation: CRISPR screen identifies neddylation/NAE1 as a cisplatin resistance mechanism and MLN4924 as a potential therapeutic agent.

[PMID:37175579] [INDIRECT EVIDENCE] [SUPPORT] a subset of patients develops cisplatin resistance, for whom additional therapeutic options are unsuccessful, and ~20% of them will die from disease progression at an early age --- Explanation: Confirms that a subset of TGCT patients develops cisplatin resistance with poor prognosis.


MONDO:0010108

[PMID:38791003] [INDIRECT EVIDENCE] [SUPPORT] DNA methylation was the first revelation in this particular field, and it continues to be a main target of investigations as research into its association with TGCT has contributed to a better understanding of this type of cancer --- Explanation: Confirms the central role of DNA methylation in TGCT pathogenesis and subtype differentiation.

[PMID:36835562] [INDIRECT EVIDENCE] [SUPPORT] Epigenetic mechanisms, such as methylations of cytosines on the DNA string and methylations and acetylations of histone 3 lysines, regulate expression of these driver genes between the TGCT subtypes --- Explanation: Confirms epigenetic mechanisms regulate driver gene expression differences between TGCT subtypes.


MAXO:0000647

[PMID:37891379] [SUPPORT] metastatic testicular germ cell tumors (TGCT) are cured in over 80% of patients using cisplatin-based combination therapy --- Explanation: Confirms the >80% cure rate with cisplatin-based combination therapy for metastatic TGCT.

[PMID:37820296] [SUPPORT] Excellent outcomes, even in widely metastatic disease using cisplatin-based chemotherapy, can be achieved since Einhorn and Donohue's landmark 1977 study in TGCT --- Explanation: Confirms excellent outcomes with cisplatin-based chemotherapy in metastatic TGCT.


MAXO:0000950

[PMID:37967143] [SUPPORT] 258 patients with testicular CSI GCT were prospectively followed by surveillance for a median time of 18 months with serial measurements of serum M371 levels, in addition to standard diagnostic techniques --- Explanation: Describes prospective surveillance protocol for stage I TGCT.


MAXO:0000014


HGNC.SYMBOL:KIT

[PMID:38541652] [SUPPORT] several genomic and transcriptomic assays have identified a few significantly mutated somatic genes, primarily KIT and K-RAS --- Explanation: Identifies KIT as one of the primary significantly mutated genes in TGCTs.


HGNC.SYMBOL:KRAS

[PMID:38541652] [SUPPORT] several genomic and transcriptomic assays have identified a few significantly mutated somatic genes, primarily KIT and K-RAS --- Explanation: Identifies K-RAS as one of the primary significantly mutated genes in TGCTs.


HGNC.SYMBOL:Isochromosome 12p


HGNC.SYMBOL:TP53

[PMID:37891379] [SUPPORT] Immunoblotting experiments revealed p53 to be induced in TTC, but not bladder cancer cells following cisplatin --- Explanation: Demonstrates functional p53 induction in testis tumor cells after cisplatin treatment, consistent with wild-type p53 in most TGCTs.


MONDO:0005526

[PMID:40543524] [PARTIAL] C tetani releases a potent neurotoxin, causing muscle spasms, rigidity, and dysautonomia. --- Explanation: Masseter spasm (trismus) represents the cranial manifestation of the generalized muscle spasms described.


MONDO:0005526

[PMID:40543524] [SUPPORT] C tetani releases a potent neurotoxin, causing muscle spasms, rigidity, and dysautonomia. --- Explanation: Highlights toxin-driven generalized rigidity.


MONDO:0005526

[PMID:40543524] [PARTIAL] C tetani releases a potent neurotoxin, causing muscle spasms, rigidity, and dysautonomia. --- Explanation: Describes the diffuse spasms that produce opisthotonic posturing.


MONDO:0005526

[PMID:40543524] [PARTIAL] C tetani releases a potent neurotoxin, causing muscle spasms, rigidity, and dysautonomia. --- Explanation: Confirms stimulus-sensitive spasms as a hallmark manifestation.


MONDO:0005526

[PMID:40543524] [NO_EVIDENCE] C tetani releases a potent neurotoxin, causing muscle spasms, rigidity, and dysautonomia. --- Explanation: Upper airway and bulbar spasms impede swallowing, leading to dysphagia.


MONDO:0005526

[PMID:40543524] [SUPPORT] Important complications include laryngeal spasm and resultant airway obstruction and respiratory arrest. --- Explanation: Links laryngospasm to respiratory failure.


MONDO:0005526

[PMID:35333944] [INDIRECT EVIDENCE] [PARTIAL] Tetanus and botulinum neurotoxins cause the neuroparalytic syndromes of tetanus and botulism, respectively, by delivering inside different types of neurons, metalloproteases specifically cleaving the SNARE proteins that are essential for the release of neurotransmitters. --- Explanation: This review confirms the mechanism of tetanus toxin action through metalloprotease cleavage of SNARE proteins, blocking neurotransmitter release.


MONDO:0005526


MONDO:0005526

[PMID:40543524] [INDIRECT EVIDENCE] [SUPPORT] C tetani releases a potent neurotoxin, causing muscle spasms, rigidity, and dysautonomia. --- Explanation: Links tetanospasmin to dysautonomia underlying cardiovascular instability.


MAXO:0000058

[PMID:40543524] [PARTIAL] Treatment is multifaceted, requiring source control, antibiotic therapy, and antitoxin administration. --- Explanation: Antitoxin (TIG) is a core component of recommended management.


MAXO:0000004

[PMID:40543524] [PARTIAL] Treatment is multifaceted, requiring source control, antibiotic therapy, and antitoxin administration. --- Explanation: Debridement provides the source control described in standard care.


MAXO:0000058

[PMID:40543524] [SUPPORT] Treatment is multifaceted, requiring source control, antibiotic therapy, and antitoxin administration. --- Explanation: Confirms antibiotics as part of standard tetanus management.


MAXO:0000058

[PMID:38822438] [PARTIAL] these studies have shown potential benefits of treating tetanus infections with benzodiazepines, magnesium sulfate and baclofen --- Explanation: This case report reviews evidence supporting the use of benzodiazepines as part of tetanus treatment.


MAXO:0000950

[PMID:40543524] [SUPPORT] With prolonged, quality intensive care, many patients survive with good functional outcome. --- Explanation: Highlights the importance of ICU-level supportive care for survival.


MAXO:0001017

[PMID:34790820] [PARTIAL] The pooled estimate of receiving at least two doses of tetanus toxoid immunization coverage in Ethiopia was 52.2% (95% CI: 42.47-61.93, I 2 = 98.4%). --- Explanation: Underscores need for vaccination and boosters due to incomplete coverage.


MONDO:0041996

[PMID:14579545] [SUPPORT] The major manifestations of toxicity consist of a rapidly progressive, ascending, extremely painful sensory neuropathy and alopecia. --- Explanation: Directly supports painful ascending peripheral neuropathy as a frequent hallmark phenotype.


MONDO:0041996

[PMID:6338655] [SUPPORT] In humans the most characteristic sign of thallium toxicity is alopecia which usually appears in cases when death is delayed for 15-20 days. --- Explanation: Supports alopecia as the most characteristic delayed cutaneous sign of thallium poisoning.


MONDO:0041996

[PMID:33438838] [SUPPORT] We found that polyneuropathy (82%), alopecia (68%), and abdominal pain (51%) were the most frequent clinical manifestations --- Explanation: Supports abdominal pain as one of the most frequent reported manifestations in thallium poisoning cases.


MONDO:0041996

[PMID:14579545] [SUPPORT] Unlike exposure to most metal salts, gastrointestinal symptoms of thallium toxicity are relatively minor, and constipation is more characteristic than diarrhoea. --- Explanation: Supports constipation as a characteristic gastrointestinal phenotype in thallium toxicity.


MONDO:0041996

[PMID:14579545] [SUPPORT] Many other findings such as an autonomic neuropathy, cranial nerve abnormalities, altered mental status, motor weakness, cardiac, hepatic, and renal effects are described, but are less specific. --- Explanation: Supports altered mental status as a recognized but less specific neurologic manifestation.


MONDO:0041996

[PMID:14579545] [INDIRECT EVIDENCE] [SUPPORT] Thallium salts are rapidly and nearly completely absorbed by virtually all routes, with gastrointestinal exposure being the most common route to produce toxicity. --- Explanation: Supports efficient thallium absorption and the importance of gastrointestinal exposure in establishing poisoning.


MONDO:0041996


MONDO:0041996

[PMID:31335706] [INDIRECT EVIDENCE] [SUPPORT] Thallium compounds can accumulate in the human body and be rapidly distributed throughout it, including in the skin and hair. --- Explanation: Directly supports widespread systemic distribution of thallium after absorption.


MONDO:0041996

[PMID:14579545] [INDIRECT EVIDENCE] [SUPPORT] Thallium enters cells by a unique process governed by its similarity in charge and ionic radius to potassium. --- Explanation: Directly supports potassium-mimetic cellular uptake as a core toxicokinetic mechanism.


MONDO:0041996

[PMID:14579545] [INDIRECT EVIDENCE] [SUPPORT] thallium interferes with energy production at essential steps in glycolysis, the Krebs cycle, and oxidative phosphorylation. --- Explanation: Supports mitochondrial and cytosolic bioenergetic failure as a central mechanism of thallium toxicity.


MONDO:0041996

[PMID:14579545] [INDIRECT EVIDENCE] [SUPPORT] Additional effects include inhibition of sodium-potassium-adenosine triphosphatase --- Explanation: Directly supports sodium-potassium ATPase inhibition as a distinct toxic mechanism in thallium poisoning.


MONDO:0041996

[PMID:14579545] [INDIRECT EVIDENCE] [SUPPORT] The major manifestations of toxicity consist of a rapidly progressive, ascending, extremely painful sensory neuropathy and alopecia. --- Explanation: Supports painful ascending sensory neuropathy as the dominant neurologic expression of thallium toxicity.

[PMID:33438838] [INDIRECT EVIDENCE] [SUPPORT] Neurologic damage represented the main sequelae of thallium poisoning in our present case report. --- Explanation: Supports persistent neurologic injury as an important consequence of thallium neurotoxicity.


MONDO:0041996

[PMID:14579545] [INDIRECT EVIDENCE] [SUPPORT] Many other findings such as an autonomic neuropathy, cranial nerve abnormalities, altered mental status, motor weakness, cardiac, hepatic, and renal effects are described, but are less specific. --- Explanation: Supports autonomic and central neurologic toxicity as a distinct branch of thallium poisoning.

[PMID:31335706] [INDIRECT EVIDENCE] [SUPPORT] Some patients with delayed admission had significant symptoms associated with central nervous system damage --- Explanation: Supports central nervous system injury as a clinically important branch in delayed or severe poisoning.


MONDO:0041996

[PMID:28761262] [INDIRECT EVIDENCE] [SUPPORT] Thallium does not have an internal anatomic reservoir, but has an affinity to keratin. --- Explanation: Supports keratin affinity and appendage accumulation as a distinct toxic branch.


MONDO:0041996

[PMID:28761262] [INDIRECT EVIDENCE] [SUPPORT] A trichogram revealed 95% of the hairs in dystrophic anagen status --- Explanation: Supports direct hair follicle injury with dystrophic anagen changes in thallium poisoning.


MAXO:0000071

[PMID:36537175] [SUPPORT] An adequate clinical approach can facilitate early diagnosis. --- Explanation: Supports the clinical importance of early recognition, which is necessary for prompt removal from exposure and source control.


MAXO:0000217

[PMID:14579545] [SUPPORT] Prussian blue's safety profile is superior to that of other proposed therapies and it should be considered the drug of choice in acute thallium poisoning. --- Explanation: Directly supports Prussian blue as the preferred antidotal treatment in acute poisoning.

[PMID:33438838] [SUPPORT] After Prussian blue treatment, thallium was undetectable in the blood by day 60. --- Explanation: Human case evidence supports effective thallium clearance during Prussian blue treatment.


MAXO:0000950

[PMID:14579545] [SUPPORT] The use of single- or multiple-dose activated charcoal is supported by in vitro binding experiments and some animal data --- Explanation: Supports activated charcoal as an adjunctive decontamination strategy, though the evidence base is indirect.


MAXO:0000058

[PMID:6338655] [SUPPORT] The current therapy for thallium poisoning is the use of prussian blue and potassium chloride. --- Explanation: Supports potassium chloride as part of established treatment regimens for thallium poisoning.

[PMID:6338655] [SUPPORT] Potassium therapy is probably the single most effective agent in the treatment of thallium poisoning. --- Explanation: Supports historical therapeutic use of potassium therapy to enhance elimination.


MAXO:0000602

[PMID:14579545] [PARTIAL] charcoal haemoperfusion may be a useful adjunct. --- Explanation: Supports extracorporeal elimination as an adjunctive rather than definitive therapy.


ECTO:9001312

[PMID:14579545] [SUPPORT] Thallium salts have been used as medicinal agents, as key ingredients in a variety of manufacturing processes, and as a potent rodenticide. --- Explanation: Supports industrial thallium salts as an important exposure source.


ECTO:9001312

[PMID:14579545] [SUPPORT] Thallium salts have been used as medicinal agents, as key ingredients in a variety of manufacturing processes, and as a potent rodenticide. --- Explanation: Supports rodenticide use as a recognized exposure source for thallium poisoning.


ECTO:9001312

[PMID:14579545] [SUPPORT] environmental concerns are growing, as thallium is a waste product of coal combustion and the manufacturing of cement. --- Explanation: Supports coal combustion and cement manufacturing as environmental contamination sources.


ECTO:9001312

[PMID:28761262] [SUPPORT] Here, we report a case of acute, nonintentional thallium poisoning due to thallium-contaminated alternative medicine --- Explanation: Directly supports contaminated alternative medicine as a real-world exposure source.


ECTO:9001312

[PMID:33438838] [SUPPORT] Following this investigation, a criminal suspect confessed to two instances of adulterating thallium sulfate in the patient's beverage. --- Explanation: Supports deliberate beverage adulteration as a documented exposure scenario.


MONDO:0008546

[PMID:7773297] [SUPPORT] Thanatophoric dysplasia (TD), the most common neonatal lethal skeletal dysplasia, affects one out of 20,000 live births. Affected individuals display features similar to those seen in homozygous achondroplasia. --- Explanation: TD is defined as a lethal skeletal dysplasia with features similar to severe (homozygous) achondroplasia, indicating extreme short-limbed dwarfism.


MONDO:0008546

[PMID:8845844] [SUPPORT] In the most common subtype (TD1), femurs are curved, while in TD2, straight femurs are associated with cloverleaf skull. --- Explanation: Curved femurs are the hallmark distinguishing TD1 from TD2.


MONDO:0008546

[PMID:20301540] [SUPPORT] Other features common to type 1 and type 2 include: short ribs, narrow thorax, relative macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. --- Explanation: GeneReviews lists short ribs as a feature common to both TD1 and TD2.


MONDO:0008546

[PMID:8845844] [SUPPORT] Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. --- Explanation: Reduced thoracic cavity is a defining clinical feature of TD.


MONDO:0008546

[PMID:8845844] [SUPPORT] Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. --- Explanation: Platyspondyly is a defining feature of thanatophoric dysplasia.


MONDO:0008546

[PMID:20301540] [SUPPORT] Other features common to type 1 and type 2 include: short ribs, narrow thorax, relative macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. --- Explanation: GeneReviews lists brachydactyly as a feature common to both TD1 and TD2.


MONDO:0008546

[PMID:8845844] [SUPPORT] Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. --- Explanation: Macrocephaly is a defining feature of thanatophoric dysplasia.

[PMID:9887329] [SUPPORT] the retardation of bone growth became more severe and showed phenotypes resembling those of achondroplasia patients, characterized by a dramatically reduced proliferation of growth plate cartilage, macrocephaly and shortening of the long bones --- Explanation: FGFR3 K644E knock-in mice recapitulate macrocephaly, supporting FGFR3 gain-of-function as the mechanism.


MONDO:0008546

[PMID:20301540] [SUPPORT] Other features common to type 1 and type 2 include: short ribs, narrow thorax, relative macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. --- Explanation: GeneReviews describes distinctive facial features as a defining TD characteristic; frontal bossing is a well-established component.


MONDO:0008546

[PMID:20301540] [SUPPORT] Other features common to type 1 and type 2 include: short ribs, narrow thorax, relative macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. --- Explanation: Midface retrusion is part of the distinctive facial features described in GeneReviews as common to TD1 and TD2.


MONDO:0008546

[PMID:20301540] [SUPPORT] Other features common to type 1 and type 2 include: short ribs, narrow thorax, relative macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. --- Explanation: Depressed nasal bridge is part of the distinctive facial features described in GeneReviews as common to TD1 and TD2.


MONDO:0008546

[PMID:8845844] [SUPPORT] In the most common subtype (TD1), femurs are curved, while in TD2, straight femurs are associated with cloverleaf skull. --- Explanation: Cloverleaf skull is the hallmark of TD2 but may uncommonly occur in TD1.


MONDO:0008546

[PMID:8845844] [SUPPORT] Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. --- Explanation: The reduced thoracic cavity directly causes respiratory insufficiency, which is the primary cause of perinatal death in TD.


MONDO:0008546

[PMID:20301540] [SUPPORT] Other features common to type 1 and type 2 include: short ribs, narrow thorax, relative macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. --- Explanation: GeneReviews lists hypotonia as a feature common to both TD1 and TD2.


MONDO:0008546

[PMID:20301540] [SUPPORT] Other features common to type 1 and type 2 include: short ribs, narrow thorax, relative macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. --- Explanation: GeneReviews lists redundant skin folds along the limbs as a defining TD feature.


MONDO:0008546

[PMID:20301540] [SUPPORT] treatment goals are to avoid potential pregnancy complications including prematurity, polyhydramnios, malpresentation, and delivery complications from macrocephaly --- Explanation: GeneReviews identifies polyhydramnios as a pregnancy complication associated with TD.


MONDO:0008546

[PMID:8845844] [INDIRECT EVIDENCE] [SUPPORT] Two novel missense mutations (Y373C and G370C) were detected in 8/26 and 1/26 TD1 cases respectively. Both mutations created cysteine residues in the juxta extramembrane domain of the receptor. --- Explanation: Demonstrates that TD1 mutations create unpaired cysteine residues enabling aberrant disulfide bonding and constitutive receptor activation.

[PMID:7773297] [INDIRECT EVIDENCE] [SUPPORT] Of 39 individuals with a second type of TD, 22 had a mutation causing an Arg248Cys change and one had a Ser371Cys substitution, both in the extracellular region of the protein. --- Explanation: Identifies R248C as the most common TD1 mutation and confirms TD1 mutations cluster in the extracellular domain of FGFR3.


MONDO:0008546


MONDO:0008546

[PMID:9582336] [INDIRECT EVIDENCE] [SUPPORT] Early ERKs activation following FGF 9 supplementation was observed in TD chondrocytes (2 min) as compared with controls (5 min) but no signal was detected in the absence of ligand. --- Explanation: Cultured TD1 chondrocytes show accelerated ERK activation upon FGF stimulation compared to controls, indicating enhanced MAPK signaling.


MONDO:0008546

[PMID:9582336] [INDIRECT EVIDENCE] [SUPPORT] ligand-independent activation of the STAT signaling pathway was demonstrated in cultured TD cells --- Explanation: Ligand-independent STAT activation in cultured human TD1 chondrocytes demonstrates cell-autonomous STAT pathway engagement.

[PMID:9582336] [INDIRECT EVIDENCE] [SUPPORT] confirmed by immunodetection of Stat 1 in the nuclei of hypertrophic TD chondrocytes --- Explanation: STAT1 nuclear localization confirmed in hypertrophic chondrocytes from TD fetal tissue sections, providing direct human clinical evidence.

[PMID:9887329] [INDIRECT EVIDENCE] [SUPPORT] expression of the mutant receptor caused the activation of Stat1, Stat5a and Stat5b, and the up-regulation of p16, p18 and p19 cell cycle inhibitors, leading to dramatic expansion of the resting zone of chondrocytes at the expense of the proliferating chondrocytes. --- Explanation: FGFR3 K644E knock-in mouse demonstrates STAT1/5 activation and ink4 cell cycle inhibitor upregulation. Proliferative arrest is demonstrated in this homozygous mouse model (TD2-equivalent mutation) but has not been confirmed in human TD1 cells.


MONDO:0008546

[PMID:9811582] [INDIRECT EVIDENCE] [SUPPORT] FGFR3 downregulated the Indian hedgehog (Ihh) signaling pathway and Bmp4 expression in both growth plate chondrocytes and in the perichondrium. --- Explanation: Activated FGFR3 transgenic mouse demonstrates suppression of IHH signaling and BMP4 expression, establishing FGFR3 as an upstream negative regulator of the hedgehog pathway in growth plate.


MONDO:0008546

[PMID:9582336] [INDIRECT EVIDENCE] [SUPPORT] these results indicate that FGFR 3 mutations in TD I fetuses do not hamper chondrocyte proliferation but rather alter their differentiation by triggering premature apoptosis through activation of the STAT signaling pathway. --- Explanation: Key finding from human TD1 fetal tissue: the primary defect is altered differentiation and premature apoptosis, not impaired proliferation.

[PMID:9811582] [INDIRECT EVIDENCE] [SUPPORT] FGFR3 inhibited endochondral bone growth by markedly inhibiting chondrocyte proliferation and by slowing chondrocyte differentiation. --- Explanation: Activated FGFR3 transgenic mouse shows both proliferation inhibition and slowed differentiation. The proliferation effect is confirmed in mouse models but not in human TD1 cells.


MONDO:0008546

[PMID:9582336] [INDIRECT EVIDENCE] [SUPPORT] the presence of an increased number of apoptotic chondrocytes in TD fetuses was associated with a higher expression of Bax and the simultaneous decrease of Bcl-2 levels. --- Explanation: Direct evidence from human TD fetal tissue demonstrating increased apoptosis with Bax/Bcl-2 imbalance in growth plate chondrocytes.


MONDO:0008546

[PMID:9811582] [INDIRECT EVIDENCE] [PARTIAL] the resulting transgenic mice are dwarfed, with axial, appendicular and craniofacial skeletal hypoplasia. --- Explanation: Activated FGFR3 transgenic mice show craniofacial skeletal hypoplasia, supporting craniofacial involvement as a direct consequence of FGFR3 gain-of-function signaling.


MONDO:0008546

[PMID:8845844] [INDIRECT EVIDENCE] [SUPPORT] Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. --- Explanation: Reduced thoracic cavity is a defining feature of TD, and mechanical restriction of lung growth is the established cause of lethality.


MAXO:0000950

[PMID:20301540] [SUPPORT] Most individuals with TD die in the perinatal period because of the multisystem complications of the disorder. Management goals should be established with the family and may focus on provision of comfort care. Newborns require long-term respiratory support (typically with tracheostomy and ventilation) to survive. --- Explanation: GeneReviews describes the standard management approach for TD including comfort care and respiratory support for potential long-term survivors.


MAXO:0000058

[PMID:25231866] [SUPPORT] statins could correct the degraded cartilage in both chondrogenically differentiated TD1 and ACH iPSCs. Treatment of ACH model mice with statin led to a significant recovery of bone growth. These results suggest that statins could represent a medical treatment for infants and children with TD1 and ACH. --- Explanation: Statins rescued cartilage defects in TD1 iPSC-derived chondrocytes and improved bone growth in an FGFR3-mutant mouse model.


hgnc:3690

[PMID:7773297] [SUPPORT] Of 39 individuals with a second type of TD, 22 had a mutation causing an Arg248Cys change and one had a Ser371Cys substitution, both in the extracellular region of the protein. None of these mutations were found in 50 controls showing that mutations affecting different functional domains of FGFR3 cause different forms of this lethal disorder. --- Explanation: Original identification of FGFR3 mutations as the cause of TD, with R248C as the most common TD1 mutation.

[PMID:8845844] [SUPPORT] Two novel missense mutations (Y373C and G370C) were detected in 8/26 and 1/26 TD1 cases respectively. Both mutations created cysteine residues in the juxta extramembrane domain of the receptor. Sixteen cases carried the previously reported R248C (9/26 cases), S249C (2/26 cases) or stop codon FGFR3 mutations (5/26 cases). --- Explanation: Comprehensive mutation spectrum of TD1 showing R248C (35%), Y373C (31%), stop codon mutations (19%), S249C (8%), and G370C (4%) among 26 TD1 cases.


MONDO:0008546

[PMID:7773297] [SUPPORT] A sporadic mutation causing a Lys650Glu change in the tyrosine kinase domain of FGFR3 was found in 16 of 16 individuals with one type of TD. Of 39 individuals with a second type of TD, 22 had a mutation causing an Arg248Cys change and one had a Ser371Cys substitution, both in the extracellular region of the protein. --- Explanation: All TD mutations found are heterozygous and sporadic (de novo), consistent with autosomal dominant inheritance with complete penetrance.


MONDO:0008547

[PMID:8845844] [SUPPORT] Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. --- Explanation: Classic clinical description confirming micromelic limb shortening as a defining feature of thanatophoric dysplasia.


MONDO:0008547

[PMID:8845844] [SUPPORT] In the most common subtype (TD1), femurs are curved, while in TD2, straight femurs are associated with cloverleaf skull. --- Explanation: Defines straight femurs as the distinguishing TD2 radiographic feature.

[PMID:21204232] [SUPPORT] the femur, which appears curved in TD1, while it remains straight but with a proximal medial spike in TD2 --- Explanation: Adds the proximal medial spike detail for TD2 femur morphology.


MONDO:0008547

[PMID:8845844] [SUPPORT] in TD2, straight femurs are associated with cloverleaf skull. --- Explanation: Establishes the association of cloverleaf skull with TD2 specifically.


MONDO:0008547

[PMID:8845844] [SUPPORT] Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. --- Explanation: Confirms reduced thoracic cavity as a core TD feature.


MONDO:0008547

[PMID:8845844] [SUPPORT] Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. --- Explanation: Confirms platyspondyly as a core feature.


MONDO:0008547

[PMID:8845844] [SUPPORT] Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. --- Explanation: Confirms macrocephaly as a core TD feature.


MONDO:0008547


MONDO:0008547

[PMID:34597445] [SUPPORT] All individuals required assisted ventilation. --- Explanation: Study of 20 long-term TD survivors confirms universal requirement for ventilatory support.


MONDO:0008547

[PMID:29458880] [SUPPORT] Fetuses with TD2 may present increased NT, early onset hydrocephalus, enlarged cerebellum and cisterna magna, and hydrancephaly on prenatal ultrasound. --- Explanation: Documents the spectrum of prenatal brain findings in TD2 including early onset hydrocephalus and hydrancephaly.


MONDO:0008547

[PMID:18923003] [SUPPORT] spinal canal and foramen magnum stenosis can cause serious neurologic complications --- Explanation: Establishes foramen magnum stenosis as a clinically significant feature of FGFR3 chondrodysplasias including TD.


MONDO:0008547

[PMID:34597445] [SUPPORT] All individuals showed severely delayed psychomotor development. The highest level of psychosocial development was equivalent to that at 2 years of age. --- Explanation: Characterizes the developmental ceiling in surviving TD individuals.


MONDO:0008547

[PMID:34597445] [SUPPORT] The mean length at birth was 36 cm (-3.4 SD to -7.9 SD). The adult height (age >16 years) was <-15.2 SD. --- Explanation: Quantifies the extreme growth deficiency in TD survivors.


MONDO:0008547

[PMID:34597445] [SUPPORT] Skin disorders (acanthosis nigricans and seborrheic keratoses) were common. --- Explanation: Documents acanthosis nigricans in TD long-term survivors, a finding shared with the related FGFR3 K650M SADDAN phenotype.


MONDO:0008547

[PMID:23972473] [INDIRECT EVIDENCE] [SUPPORT] the mutation introduces a network of intramolecular hydrogen bonds to stabilize the active-state conformation --- Explanation: Crystal structure of FGFR3 K650E shows the mutation mimics A-loop phosphorylation, providing the structural basis for constitutive activation.

[PMID:23972473] [INDIRECT EVIDENCE] [SUPPORT] the K650E mutation circumvents the requirement for A-loop tyrosine phosphorylation in kinase activation --- Explanation: Biochemical and structural analysis demonstrates that K650E confers ligand-independent and phosphorylation-independent kinase activity.


MONDO:0008547

[PMID:14751560] [INDIRECT EVIDENCE] [SUPPORT] Abnormally high amounts of Stat1, Stat5 and p21Cip1 proteins were found in prehypertrophic-hypertrophic chondrocytes, the extent of overexpression being directly related to the severity of the disease. --- Explanation: Direct human fetal growth plate analysis showing severity-correlated STAT/p21 overexpression across ACH and TD, with TD most severe.

[PMID:14751560] [INDIRECT EVIDENCE] [SUPPORT] defective differentiation of chondrocytes is the main cause of longitudinal bone growth retardation in FGFR3-related human chondrodysplasias --- Explanation: Demonstrates that chondrocyte differentiation defect (not proliferation alone) is the primary mechanism.

[PMID:9887329] [INDIRECT EVIDENCE] [SUPPORT] expression of the mutant receptor caused the activation of Stat1, Stat5a and Stat5b, and the up-regulation of p16, p18 and p19 cell cycle inhibitors, leading to dramatic expansion of the resting zone of chondrocytes at the expense of the proliferating chondrocytes --- Explanation: Mouse knock-in model with the equivalent K644E mutation directly demonstrates STAT and ink4 upregulation causing growth plate disruption.


MONDO:0008547

[PMID:15843401] [INDIRECT EVIDENCE] [SUPPORT] sustained activation of ERK1/2 and activation of STAT1 and STAT3, but not STAT5, is observed in the absence of ligand --- Explanation: PC12 cells expressing the TDII K650E mutation show constitutive ligand-independent ERK1/2 and STAT activation.

[PMID:15843401] [INDIRECT EVIDENCE] [SUPPORT] Silencing of STAT1 or 3 independently or in combination had no significant effect on ligand-independent neurite outgrowth, ERK1/2 activation or p21(WAF1/CIP1) protein levels --- Explanation: STAT1/3 knockdown does not block the differentiation phenotype, establishing ERK1/2 as the key pathway for premature differentiation.

[PMID:20034074] [INDIRECT EVIDENCE] [SUPPORT] The signal transducers and activators of transcription (STAT1) pathway is involved in the inhibition of chondrocyte proliferation, and the mitogen-activated protein kinase (MAPK) pathways are involved in chondrocyte differentiation. --- Explanation: Review article summarizing that STAT1 mediates proliferation inhibition while MAPK mediates differentiation effects in FGFR3 chondrodysplasias.


MONDO:0008547

[PMID:9582336] [INDIRECT EVIDENCE] [SUPPORT] the presence of an increased number of apoptotic chondrocytes in TD fetuses was associated with a higher expression of Bax and the simultaneous decrease of Bcl-2 levels --- Explanation: Direct observation of increased apoptosis with pro-apoptotic Bax/Bcl-2 shift in human TD fetal growth plate chondrocytes.

[PMID:9582336] [INDIRECT EVIDENCE] [SUPPORT] FGFR 3 mutations in TD I fetuses do not hamper chondrocyte proliferation but rather alter their differentiation by triggering premature apoptosis through activation of the STAT signaling pathway --- Explanation: Establishes that apoptosis (not proliferation defect) is the primary cellular consequence in TD, mediated by STAT signaling.

[PMID:17561467] [INDIRECT EVIDENCE] [SUPPORT] the constitutively active forms of FGFR3 (TDII-FGFR3) and STAT1 (STAT1-C) induce apoptosis of chondrogenic ATDC5 cells via caspase activity --- Explanation: Demonstrates that TDII-FGFR3 specifically induces apoptosis through the PLCgamma-STAT1 pathway in chondrogenic cells.


MONDO:0008547

[PMID:22843502] [INDIRECT EVIDENCE] [SUPPORT] the mutant receptor caused a block in chondrocyte differentiation specifically at the prehypertrophic stage --- Explanation: TD2 mouse model shows FGFR3 K650E blocks chondrocyte maturation at the prehypertrophic stage.

[PMID:22843502] [INDIRECT EVIDENCE] [SUPPORT] The differentiation block and defects in joint formation are associated with persistent expression of the chondrogenic factor Sox9 and down-regulation of β-catenin levels and activity in growth plate chondrocytes --- Explanation: Identifies Sox9 stabilization and beta-catenin loss as the molecular circuit disrupted by K650E FGFR3 in the TD2 mouse model.

[PMID:22843502] [INDIRECT EVIDENCE] [SUPPORT] The differentiation block led to a severe reduction in hypertrophic chondrocytes that normally produce vascular endothelial growth factor --- Explanation: Links the chondrocyte differentiation block to impaired VEGF production and defective ossification center vascularization.


MONDO:0008547

[PMID:18923003] [INDIRECT EVIDENCE] [SUPPORT] FGFR3 and MAPK signaling in chondrocytes promote synchondrosis closure and fusion of ossification centers --- Explanation: Demonstrates that FGFR3-MAPK drives premature synchondrosis closure in cranial base and spine, directly explaining foramen magnum stenosis.

[PMID:18923003] [INDIRECT EVIDENCE] [SUPPORT] FGF signaling in chondrocytes increases Bmp ligand mRNA expression and decreases Bmp antagonist mRNA expression in a MAPK-dependent manner --- Explanation: Identifies BMP pathway modulation as the MAPK-dependent mechanism driving accelerated ossification center fusion.

[PMID:18923003] [INDIRECT EVIDENCE] [SUPPORT] premature synchondrosis closure in the spine and cranial base in human cases of homozygous achondroplasia and thanatophoric dysplasia --- Explanation: Confirms premature synchondrosis closure in human TD cases, not just mouse models.

[PMID:21204232] [INDIRECT EVIDENCE] [SUPPORT] we consider encephaloceles described in TD to be pseudoencephaloceles, since they are secondary to the intracranial pressure generated by severe hydrocephaly and to severe cranial structural anomalies --- Explanation: Clarifies that brain herniation in TD2 results from intracranial pressure due to craniosynostosis and hydrocephalus.


MONDO:0008547

[PMID:8845844] [INDIRECT EVIDENCE] [SUPPORT] Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. --- Explanation: Confirms the reduced thoracic cavity that restricts lung growth and causes the pulmonary hypoplasia responsible for perinatal lethality.


MONDO:0008547

[PMID:33116259] [INDIRECT EVIDENCE] [SUPPORT] GOF disrupts mitosis of radial-glia neural progenitors (RGCs), inside-out radial migration of post-mitotic glutamatergic neurons, and axonal tract projections --- Explanation: Mouse model expressing FGFR3 K650E in neurons demonstrates direct CNS effects including neuronal migration and axonal guidance defects.

[PMID:21204232] [INDIRECT EVIDENCE] [SUPPORT] FGF ligands and receptors (including FGFR3) act in concert to organize the whole telencephalon activity, rather than independently patterning different areas --- Explanation: FGFR3 has direct roles in telencephalic patterning, supporting the notion that K650E gain-of-function causes primary brain malformations.


MAXO:0000950

[PMID:34597445] [SUPPORT] Long-term survival of TD individuals is common. Some individuals enjoy home-based lives; however, they are severely psychosocially and physically disabled and require meticulous respiratory and nutritional support. --- Explanation: Characterizes the intensive supportive care needs of TD long-term survivors.


MAXO:0000058

[PMID:25231866] [SUPPORT] statins could correct the degraded cartilage in both chondrogenically differentiated TD1 and ACH iPSCs. Treatment of ACH model mice with statin led to a significant recovery of bone growth. --- Explanation: Preclinical evidence for statin rescue of FGFR3 skeletal dysplasia phenotypes, including in TD1 iPSC-derived chondrocytes.


hgnc:3690

[PMID:7773297] [SUPPORT] A sporadic mutation causing a Lys650Glu change in the tyrosine kinase domain of FGFR3 was found in 16 of 16 individuals with one type of TD. --- Explanation: Original identification of the K650E mutation in all 16 TD2 cases.

[PMID:8845844] [SUPPORT] While TD2 was accounted for by a single recurrent mutation in the tyrosine kinase 2 domain, TD1 resulted from either stop codon mutations or missense mutations in the extracellular domain of the gene. --- Explanation: Confirms TD2 genetic homogeneity with a single recurrent tyrosine kinase domain mutation, in contrast to TD1 heterogeneity.

[PMID:21204232] [SUPPORT] the K650E mutation involving the change of a lysine to glutamic acid ("Lys650Glu") has been found in all TD2 cases to date --- Explanation: Confirms 100% genotype-phenotype correlation for K650E in TD2.


MONDO:0001249

[PMID:35618795] [SUPPORT] Trachoma is a neglected tropical disease caused by infection with conjunctival strains of Chlamydia trachomatis. It can result in blindness. --- Explanation: The abstract notes that trachoma can result in blindness.


MAXO:0000058

[PMID:35618795] [SUPPORT] Surgery is offered to individuals with trichiasis and antibiotic mass drug administration and interventions to stimulate facial cleanliness and environmental improvement are designed to reduce infection prevalence and transmission. --- Explanation: The abstract describes antibiotic mass drug administration as part of SAFE.


NCBITaxon:813

[PMID:35618795] [SUPPORT] Trachoma is a neglected tropical disease caused by infection with conjunctival strains of Chlamydia trachomatis. --- Explanation: The abstract identifies conjunctival C. trachomatis as the cause of trachoma.


MONDO:0021553

[PMID:32644728] [SUPPORT] Transverse myelitis (TM) is a rare, acquired focal inflammatory disorder often presenting with rapid onset weakness, sensory deficits, and bowel/bladder dysfunction. --- Explanation: Rapid onset weakness is a key presenting feature of transverse myelitis.


MONDO:0021553

[PMID:32644728] [SUPPORT] Transverse myelitis (TM) is a rare, acquired focal inflammatory disorder often presenting with rapid onset weakness, sensory deficits, and bowel/bladder dysfunction. --- Explanation: Sensory deficits are listed among common presenting features of transverse myelitis.


MONDO:0021553

[PMID:32644728] [SUPPORT] Transverse myelitis (TM) is a rare, acquired focal inflammatory disorder often presenting with rapid onset weakness, sensory deficits, and bowel/bladder dysfunction. --- Explanation: Bladder dysfunction is listed as a presenting feature of transverse myelitis.


MONDO:0021553

[PMID:32644728] [SUPPORT] Transverse myelitis (TM) is a rare, acquired focal inflammatory disorder often presenting with rapid onset weakness, sensory deficits, and bowel/bladder dysfunction. --- Explanation: Bowel dysfunction is listed among presenting features of transverse myelitis.


MONDO:0021553

[PMID:32644728] [SUPPORT] At peak deficit, 50% of patients are completely paraplegic, with virtually all of the patients having a degree of bladder/bowel dysfunction. --- Explanation: The abstract notes paraplegia in a substantial fraction of patients at peak deficit.


MONDO:0021553

[PMID:32644728] [INDIRECT EVIDENCE] [SUPPORT] Transverse myelitis (TM) is a rare, acquired focal inflammatory disorder often presenting with rapid onset weakness, sensory deficits, and bowel/bladder dysfunction. --- Explanation: The abstract defines transverse myelitis as a focal inflammatory disorder of the spinal cord.

[PMID:12045735] [INDIRECT EVIDENCE] [SUPPORT] Acute transverse myelitis is a group of disorders characterized by focal inflammation of the spinal cord and resultant neural injury. --- Explanation: The review describes focal spinal cord inflammation with neural injury as a defining feature.


MONDO:0021553


MONDO:0021553

[PMID:12045735] [INDIRECT EVIDENCE] [SUPPORT] In idiopathic acute transverse myelitis, there is an intraparenchymal or perivascular cellular influx into the spinal cord, resulting in the breakdown of the blood-brain barrier and variable demyelination and neuronal injury. --- Explanation: The abstract describes immune cell influx with BBB breakdown and neural injury in TM.


MAXO:0000640

[PMID:26009577] [SUPPORT] Standard treatment is steroids, and patients with more severe disease appear to respond to plasma exchange (PLEX). --- Explanation: The abstract states steroids are standard treatment for transverse myelitis.


MONDO:0001673

[PMID:35358002] [SUPPORT] Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea in children and travelers in developing countries. --- Explanation: Establishes diarrhea as the hallmark symptom of ETEC-associated traveler's diarrhea.


MONDO:0001673

[PMID:35839362] [PARTIAL] History for patients with acute diarrhea should include onset and frequency of symptoms, stool character, a focused review of systems including fever and other symptoms, and evaluation of exposures and risk factors. --- Explanation: Guidance for acute diarrhea evaluation highlights associated abdominal symptoms that accompany diarrheal illness.


MONDO:0001673

[PMID:35839362] [PARTIAL] Acute diarrheal disease accounts for 179 million outpatient visits annually in the United States... History for patients with acute diarrhea should include onset and frequency of symptoms, stool character, a focused review of systems including fever and other symptoms. --- Explanation: Clinical review notes nausea and systemic symptoms are routinely assessed with acute diarrheal illnesses.


MONDO:0001673

[PMID:35839362] [INDIRECT EVIDENCE] [SUPPORT] Infectious noninflammatory diarrhea is often viral in etiology and is the most common presentation; however, bacterial causes are also common and may be related to travel or foodborne illness. --- Explanation: Acute diarrhea review links bacterial diarrheal illness to travel and foodborne exposures.


MONDO:0001673

[PMID:38052687] [INDIRECT EVIDENCE] [SUPPORT] Colonization factors (CFs) are major virulence factors of enterotoxigenic Escherichia coli (ETEC). --- Explanation: Review highlights CFs as key adherence determinants enabling ETEC intestinal colonization.


MONDO:0001673

[PMID:35358002] [INDIRECT EVIDENCE] [SUPPORT] ETEC is characterized by the ability to produce major virulence factors including colonization factors (CFs) and enterotoxins, that bind to specific receptors on epithelial cells and induce diarrhea. --- Explanation: Review notes ETEC enterotoxins trigger receptor-mediated fluid secretion leading to diarrhea.


MAXO:0000618

[PMID:35839362] [SUPPORT] In all cases, management begins with replacing water, electrolytes, and nutrients. Oral rehydration is preferred; however, signs of severe dehydration or sepsis warrant intravenous rehydration. --- Explanation: Review emphasizes oral rehydration as first-line management for acute diarrheal illness.


MAXO:0000058

[PMID:39453259] [PARTIAL] Knowledge gaps persisted: over 50% were unaware of TD's self-limited nature, 30% did not recognize loperamide as a symptom reliever, and 36% believed all travelers should take antibiotics to prevent TD.
 --- Explanation: Pre-travel consultation study identifies loperamide as a recognized symptomatic reliever for traveler's diarrhea.


MAXO:0000058

[PMID:35839362] [PARTIAL] Empiric antibiotics are rarely warranted, except in sepsis and some cases of travelers' or inflammatory diarrhea. Targeted antibiotic therapy may be appropriate following microbiologic stool assessment. --- Explanation: Clinical review notes selective use of antibiotics, including in some traveler's diarrhea cases.

[PMID:40024692] [PARTIAL] Resistant strains to representative therapeutic agents such as ciprofloxacin and azithromycin have been reported in recent years, and multidrug-resistant ETEC has also emerged. --- Explanation: Resistance trends in ETEC underscore reserving fluoroquinolones for indicated cases and adjusting based on susceptibility.


MAXO:0000058

[PMID:32966000] [SUPPORT] Rifaximin is an antibiotic used to treat irritable bowel syndrome with diarrhea, reduce the risk of overt hepatic encephalopathy recurrence in adults, and treat travelers’ diarrhea caused by noninvasive strains of Escherichia coli. --- Explanation: StatPearls entry lists rifaximin as indicated for traveler's diarrhea from noninvasive E. coli.

[PMID:36221413] [PARTIAL] Compared with placebo, both probiotics and rifaximin were associated with lower incidence of TD (probiotics, RR 0.85, 95% CI 0.76-0.95; rifaximin, RR 0.47, 95% CI 0.35-0.63). --- Explanation: Network meta-analysis shows rifaximin reduces traveler’s diarrhea incidence more than probiotics, supporting its preventive use.


MAXO:0000058

[PMID:32809532] [PARTIAL] This educational activity focuses on bismuth subsalicylate's applications in managing gastrointestinal discomfort and traveler's diarrhea. --- Explanation: StatPearls review describes bismuth subsalicylate use for managing traveler's diarrhea symptoms.

[PMID:33064636] [PARTIAL] The antisecretory, anti-inflammatory, and antibacterial properties of bismuth make it a suitable therapy for symptomatic treatment of diarrhea. --- Explanation: Narrative review highlights bismuth’s multimodal activity for diarrheal symptom relief, including traveler’s diarrhea.


MAXO:0000058

[PMID:38458507] [SUPPORT] Based on this systematic review and meta-analysis, specific probiotic strains, including L. acidophilus, L. rhamnosus, L. fermentum, S. cerevisiae, and S. boulardii, may prevent TD. --- Explanation: Meta-analysis finds several probiotic strains reduce risk of traveler's diarrhea, supporting prophylactic use.

[PMID:36221413] [SUPPORT] Both probiotics and rifaximin were associated with lower incidence of TD (probiotics, RR 0.85, 95% CI 0.76-0.95). --- Explanation: Network meta-analysis quantifies reduced traveler’s diarrhea incidence with probiotic prophylaxis.


MAXO:0000950

[PMID:39453259] [PARTIAL] The EG/post-consultation group showed significant improvement in knowledge, with correct answers increasing from 63% to 75%... knowledge gaps persisted... indicating the need for targeted interventions to increase travelers' literacy and optimize pre-travel consultations. --- Explanation: Study shows pre-travel counseling improves knowledge about traveler’s diarrhea prevention, underscoring value of education.

[PMID:40035303] [PARTIAL] Traveling abroad carries the risk of traveler's diarrhea, which affects 20 to 50% of individuals. This article focuses on the definition, classification, epidemiology, etiology, prevention, and treatment management of traveler's diarrhea. It also describes recommendations for patients traveling to higher-risk areas, which can be used by pharmacists in counceling activities in the pharmacy. --- Explanation: Pharmacy guidance resource supports counseling travelers on prevention and treatment choices.


MAXO:0000058

[PMID:36221413] [SUPPORT] Compared with placebo, both probiotics and rifaximin were associated with lower incidence of TD (probiotics, RR 0.85, 95% CI 0.76-0.95; rifaximin, RR 0.47, 95% CI 0.35-0.63), and rifaximin was more effective than probiotics (RR 0.56, 95% CI 0.4-0.78). --- Explanation: Network meta-analysis shows rifaximin prophylaxis significantly reduces traveler’s diarrhea incidence compared with placebo and probiotics.


NCBITaxon:562


MONDO:0008270

[PMID:17152067] [SUPPORT] Four North American Caucasian families were identified with autosomal dominant triphalangeal thumb. --- Explanation: Triphalangeal thumb is the primary phenotype in families with ZRS mutations.

[PMID:18463159] [SUPPORT] We found this variant in three independently ascertained probands from southern England with triphalangeal thumb, demonstrated significant linkage of the phenotype to the variant (LOD = 4.1) --- Explanation: Significant linkage of triphalangeal thumb to ZRS variant with LOD 4.1.


MONDO:0008270

[PMID:24777739] [SUPPORT] Although most mutations cause preaxial polydactyly (PPD), triphalangeal thumb (TPT) or both, a mutation in position 404 of the ZRS causes more severe Werner mesomelic syndrome (WMS) --- Explanation: Preaxial polydactyly is a common manifestation of ZRS mutations.

[PMID:20068592] [SUPPORT] This finding supports a model in which ectopic anterior SHH expression in the developing limb results from abnormal binding of one or more transcription factors to the mutant sequence. --- Explanation: Mechanistically links ZRS mutations to ectopic SHH expression causing preaxial polydactyly.


MONDO:0008270


MONDO:0008270

[PMID:18463159] [INDIRECT EVIDENCE] [SUPPORT] we utilized a mutated ZRS construct to demonstrate that it can drive ectopic anterior expression of a reporter gene in the developing mouse forelimb. --- Explanation: Direct experimental demonstration that ZRS mutations drive ectopic anterior SHH expression in the developing limb.

[PMID:20068592] [INDIRECT EVIDENCE] [SUPPORT] Electrophoretical mobility shift assay demonstrated a marked difference between wild-type and the mutant probe, which uniquely bound one or several transcription factors extracted from Caco-2 cells. --- Explanation: ZRS mutations alter transcription factor binding, providing a molecular mechanism for ectopic enhancer activity.


MONDO:0008270

[PMID:24777739] [INDIRECT EVIDENCE] [SUPPORT] A mouse transgenic enhancer assay shows that this mutation causes an expansion of the enhancer's expression domain in the developing mouse limb, confirming its pathogenicity. --- Explanation: Expansion of enhancer expression domain confirms disrupted anterior-posterior patterning in vivo.


hgnc:10848

[PMID:17152067] [SUPPORT] Spatio-temporal expression of sonic hedgehog (SHH) is driven by a regulatory element (ZRS) that lies 1 Mb upstream from SHH. --- Explanation: Identifies the ZRS as the regulatory element controlling SHH expression and reports novel point mutations in three families with triphalangeal thumb and preaxial polydactyly.

[PMID:18463159] [SUPPORT] A locus for triphalangeal thumb, variably associated with pre-axial polydactyly, was previously identified in the zone of polarizing activity regulatory sequence (ZRS), a long range limb-specific enhancer of the Sonic Hedgehog (SHH) gene at human chromosome 7q36.3. --- Explanation: Identifies the ZRS at chromosome 7q36.3 as the regulatory locus underlying triphalangeal thumb and preaxial polydactyly in human families.

[PMID:35821352] [SUPPORT] This rare congenital limb anomaly is generally caused by microduplications encompassing the Sonic Hedgehog (SHH) limb enhancer, termed the zone of polarizing activity (ZPA) regulatory sequence (ZRS). --- Explanation: Establishes that TPT-PS is generally caused by microduplications encompassing the ZRS enhancer, providing the genetic context for this locus.


MONDO:0005494


MONDO:0005494

[PMID:35987766] [SUPPORT] Triple negative breast cancer (TNBC) is characterized by the lack of estrogen and progesterone receptor expression and lacks HER2 overexpression or gene amplification. --- Explanation: Abstract defines TNBC by lack of ER/PR and HER2, matching the diagnostic phenotype.


MONDO:0005494

[PMID:41518487] [INDIRECT EVIDENCE] [SUPPORT] Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, remains clinically challenging due to the lack of effective targeted therapies. --- Explanation: This abstract defines TNBC by the absence of ER, PR, and HER2 expression, matching the mechanism described.


MONDO:0005494

[PMID:35987766] [INDIRECT EVIDENCE] [SUPPORT] It accounts for 10-15% of incident breast cancers and carries the worst prognosis. --- Explanation: Abstract states TNBC carries the worst prognosis, supporting aggressive behavior.


MAXO:0000647

[PMID:32046998] [PARTIAL] Patients with a pCR after NAT had significantly better EFS (HR = 0.31; 95% PI, 0.24-0.39), particularly for triple-negative (HR = 0.18; 95% PI, 0.10-0.31) and HER2+ (HR = 0.32; 95% PI, 0.21-0.47) disease. --- Explanation: Meta-analysis confirms that achieving pCR after neoadjuvant therapy is strongly associated with improved event-free survival, particularly for TNBC.


MAXO:0000058

[PMID:32101663] [SUPPORT] Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. --- Explanation: KEYNOTE-522 demonstrated significantly higher pCR rates with pembrolizumab plus chemotherapy versus chemotherapy alone in early TNBC.


NCIT:C106432

[PMID:32101663] [INDIRECT EVIDENCE] [SUPPORT] Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. --- Explanation: KEYNOTE-522 demonstrated significantly higher pCR rates with pembrolizumab plus chemotherapy versus chemotherapy alone in early TNBC.


MAXO:0000058

[PMID:33475295] [PARTIAL] PARP inhibition causes synthetic lethality in breast cancers associated with germline BRCA1 and BRCA2 mutations and is routinely used in clinical practice for metastatic breast cancer. --- Explanation: Review confirms PARP inhibitors cause synthetic lethality in BRCA-mutated breast cancers and are standard of care for metastatic disease.


MAXO:0000058

[PMID:33882206] [SUPPORT] Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. --- Explanation: ASCENT trial demonstrated significant PFS and OS benefit with sacituzumab govitecan versus chemotherapy in metastatic TNBC.


NCIT:C102783

[PMID:33882206] [INDIRECT EVIDENCE] [SUPPORT] Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. --- Explanation: ASCENT trial demonstrated significant PFS and OS benefit with sacituzumab govitecan versus chemotherapy in metastatic TNBC.


MAXO:0000647

[PMID:21633166] [PARTIAL] BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. --- Explanation: Basal-like TNBC subtypes with DNA damage response gene expression preferentially respond to platinum chemotherapy.


HGNC.SYMBOL:TP53

[PMID:31045815] [SUPPORT] TP53 gene is mutated in approximately 80% of triple-negative breast cancer (TNBC). --- Explanation: Abstract reports TP53 mutation frequency in TNBC, supporting this genetic association.


HGNC.SYMBOL:BRCA1


HGNC.SYMBOL:PIK3CA


MONDO:0005494

[PMID:39806949] [PARTIAL] Invasive ductal carcinoma (IDC) is the most common type of breast cancer, --- Explanation: Abstract states that invasive ductal carcinoma is the most common breast cancer type.


MONDO:0018076

[PMID:29196066] [PARTIAL] Cough is common in pulmonary TB and other chronic respiratory infections. --- Explanation: While cough is indeed a common symptom of pulmonary TB, the statement specifically categorizes chronic cough as very frequent, which is partially supported but not explicitly confirmed by the literature.

[PMID:16131501] [SUPPORT] A persistent, non-remitting cough was reported in 15/16 (93.8%) children with tuberculosis. --- Explanation: This strongly supports the statement as it shows a high prevalence of a persistent chronic cough in children diagnosed with tuberculosis.

[PMID:35710915] [NO_EVIDENCE] Initial microbiologic burdens and radiographic features also varied, including the presence of cavities and bilateral infiltration, which reflect TB-related severity. --- Explanation: The study identifies chronic cough as a significant symptomatic characteristic among the different TB phenotypes.


MONDO:0018076

[PMID:11120618] [SUPPORT] We describe three patients with recurrent fever thought to be due to tuberculosis, and review the 14 previously reported cases who fulfil the criteria of recurrent fever for at least 1 month's duration --- Explanation: The literature indicates that fever is a frequent symptom associated with tuberculosis.

[PMID:31641790] [PARTIAL] Tuberculosis is a bacterial infectious disease that is usually transmitted by inhalation of droplets containing the bacteria. --- Explanation: While this reference does affirm that tuberculosis causes systemic issues, it does not directly specify fever as a frequent phenotype.

[PMID:18173876] [PARTIAL] SETTING: The diagnosis of tuberculosis (TB) may be rejected in the absence of symptoms such as fever, sweats or weight loss. --- Explanation: This reference notes the association of fever with tuberculosis but also highlights cases where fever may be absent, hence only partially supporting the statement.


MONDO:0018076

[PMID:31599243] [SUPPORT] Cough, night sweat, fever, anorexia were significant presenting features. --- Explanation: The study documents night sweats as a significant symptom in TB patients.

[PMID:12643362] [PARTIAL] Tuberculosis and lymphoma are diseases in which night sweats are a dominant symptom, but these are infrequently found to be the cause of night sweats in modern practice. --- Explanation: While night sweats are a notable symptom of TB, the reference suggests that in modern practice, they are less frequently the cause of night sweats compared to other conditions.

[PMID:21813327] [SUPPORT] During therapy, fever, sweats, and dyspnea decreased most rapidly, with near resolution by the end of therapy. --- Explanation: The data supports the presence of night sweats as a frequent symptom in TB, with sweats reducing significantly during therapy.


MONDO:0018076

[PMID:36451280] [SUPPORT] Tuberculosis (TB) is well-known for causing wasting. Patients on treatment gain weight and weight loss is associated with unfavorable treatment outcomes. --- Explanation: This supports the statement that weight loss is a frequently observed systemic phenotype associated with tuberculosis.

[PMID:38736083] [PARTIAL] Esophageal TB most commonly presents with dysphagia, odynophagia, retrosternal pain, and systemic symptoms like decreased appetite, loss of weight, and low-grade fever as associated or other presentations. --- Explanation: This reference supports the statement by indicating that weight loss is a common systemic symptom of esophageal tuberculosis.

[PMID:23531875] [PARTIAL] CBA/J mice may model these events, as sick mice share features with TB patients, including weight loss... --- Explanation: Although the study is on mice, it draws parallels with human TB patients, reinforcing that weight loss is a frequently observed phenotype.

[PMID:18173876] [PARTIAL] The diagnosis of tuberculosis (TB) may be rejected in the absence of symptoms such as fever, sweats or weight loss... In our population, TB, including pulmonary disease, frequently presented without fever, sweats or weight loss and with normal blood inflammatory markers. --- Explanation: This indicates that while weight loss is a known symptom, it is not always present in all TB cases, suggesting that it may be frequent but not ubiquitous.

[PMID:8623687] [SUPPORT] All patients with a positive reaction to the tuberculin skin test should be evaluated for weight loss, night sweats, fever, chronic cough and other signs of active tuberculosis. --- Explanation: This reference confirms that weight loss is one of the systemic symptoms that are frequently checked for in TB patients.


MONDO:0018076

[PMID:12816036] [SUPPORT] The most common causes of hemoptysis are tuberculosis, lung carcinoma, bronchiectasis but idiopathic forms are frequent. --- Explanation: The text states that tuberculosis is one of the most common causes of hemoptysis, supporting the statement.


MONDO:0018076

[PMID:17508531] [PARTIAL] Pleuritic chest pain is a common presenting symptom and has many causes, which range from life-threatening to benign, self-limited conditions. --- Explanation: The reference mentions pleuritic chest pain as a common symptom, but it does not specifically state that it is frequently associated with tuberculosis.

[PMID:27499981] [SUPPORT] TPE usually presents as an acute illness with fever, cough and pleuritic chest pain. --- Explanation: This reference supports the statement as it explicitly mentions that tuberculous pleural effusion (a form of extrapulmonary tuberculosis) commonly presents with pleuritic chest pain.

[PMID:30762202] [NO_EVIDENCE] Chest is the commonest site of involvement by tuberculosis (TB) in children; lungs being the most frequently affected region, followed by nodes, pleura and chest wall. --- Explanation: While this reference does not directly state chest pain, it supports the involvement of the chest in tuberculosis, which can be associated with pleuritic chest pain.

[PMID:35809948] [NO_EVIDENCE] A 50-year-old woman with a history of permanent atrial fibrillation (AF) treated with radiofrequency catheter ablation (RFCA) 6 months ago was admitted to the respiratory department of a tertiary hospital because of recurrent episodes of pleuritic chest pain in the preceding 5 months. --- Explanation: This case study mentions recurrent pleuritic chest pain, supporting the statement that chest pain is a frequent symptom in respiratory conditions, including tuberculosis.


MONDO:0018076

[PMID:15623010] [NO_EVIDENCE] Symptoms of pulmonary TB are a cough with or without sputum production lasting at least three weeks, chest pain, hemoptysis, fever, night sweats, weight loss, lack of appetite, chills and weakness. --- Explanation: The abstract mentions that dyspnea (shortness of breath) is a symptom of pulmonary tuberculosis, which supports the statement that dyspnea is occasionally associated with tuberculosis.

[PMID:29900887] [PARTIAL] Lung function impairment is known to occur after pulmonary TB irrespective of duration of treatment and outcome of disease. --- Explanation: This reference indicates that lung function issues, including dyspnea, can persist even after successful treatment of tuberculosis.


MONDO:0018076

[PMID:33645194] [NO_EVIDENCE] Sarcoidosis is a systemic granulomatous disorder of unknown cause that occurs in both men and women of all races. It typically presents in patients after 20 years of age. Sarcoidosis most frequently involves the lung, but up to 30 percent of patients present with extra-thoracic manifestations. It can involve multiple organs to a variable extent and degree. In areas, where tuberculosis is endemic, the diagnosis of sarcoidosis may be overlooked and misdiagnosed because of clinical and radiographic resemblance. --- Explanation: The abstract mentions that tuberculosis can be misdiagnosed as sarcoidosis due to similar symptoms, including fatigue, indicating that fatigue can be a systemic symptom of tuberculosis.

[PMID:35189895] [PARTIAL] Patients with chronic fatigue syndrome and post-tuberculosis experience similar symptoms. Furthermore, chronic fatigue syndrome and tuberculosis share similar plasma immunosignatures. --- Explanation: The study indicates that tuberculosis can lead to symptoms similar to chronic fatigue syndrome, supporting the statement that fatigue can be a systemic symptom of tuberculosis.