MAXO:0000058

[DOI:10.1136/bcr-2023-258290] [PARTIAL] Symptoms improved gradually with steroids and vestibular rehabilitation therapy. --- Explanation: Case of COVID-19-induced acute labyrinthitis in a teenager showing improvement with corticosteroid treatment and vestibular rehabilitation.

[DOI:10.1097/md.0000000000033889] [NO_EVIDENCE] Corticosteroids are the first-line treatment, but their responses are variable and relapses are frequent. --- Explanation: Review establishing corticosteroids as first-line therapy for autoimmune inner ear disease, though with variable responses.

[PMID:41310738] [PARTIAL] ceftriaxone sodium (2 g) and dexamethasone (10 mg) were administered via intravenous infusion once daily for 5 days, complemented by hydroxymethazoline and mometasone furoate nasal sprays as adjunctive antiinflammatory measures. Within a week, audiometric thresholds returned to normal, nystagmus intensity progressively diminished, and vertigo resolved entirely. --- Explanation: Case demonstrating complete audiometric and vestibular recovery within one week with early combination IV dexamethasone and antibiotic therapy for serous labyrinthitis.

[PMID:40225079] [PARTIAL] Despite the temporary effectiveness of corticosteroid treatment during the process, cochlear implantation was ultimately required. --- Explanation: Case showing that while corticosteroids provided temporary improvement in labyrinthitis ossificans, they were insufficient to prevent progressive hearing loss requiring cochlear implantation.


MAXO:0000058

[DOI:10.1136/bcr-2023-258290] [INDIRECT EVIDENCE] [PARTIAL] Symptoms improved gradually with steroids and vestibular rehabilitation therapy. --- Explanation: Case of COVID-19-induced acute labyrinthitis in a teenager showing improvement with corticosteroid treatment and vestibular rehabilitation.

[DOI:10.1097/md.0000000000033889] [INDIRECT EVIDENCE] [NO_EVIDENCE] Corticosteroids are the first-line treatment, but their responses are variable and relapses are frequent. --- Explanation: Review establishing corticosteroids as first-line therapy for autoimmune inner ear disease, though with variable responses.

[PMID:41310738] [INDIRECT EVIDENCE] [PARTIAL] ceftriaxone sodium (2 g) and dexamethasone (10 mg) were administered via intravenous infusion once daily for 5 days, complemented by hydroxymethazoline and mometasone furoate nasal sprays as adjunctive antiinflammatory measures. Within a week, audiometric thresholds returned to normal, nystagmus intensity progressively diminished, and vertigo resolved entirely. --- Explanation: Case demonstrating complete audiometric and vestibular recovery within one week with early combination IV dexamethasone and antibiotic therapy for serous labyrinthitis.

[PMID:40225079] [INDIRECT EVIDENCE] [PARTIAL] Despite the temporary effectiveness of corticosteroid treatment during the process, cochlear implantation was ultimately required. --- Explanation: Case showing that while corticosteroids provided temporary improvement in labyrinthitis ossificans, they were insufficient to prevent progressive hearing loss requiring cochlear implantation.


MAXO:0000058

[PMID:15269315] [REFUTE] Analysis of variance showed a significant effect of methylprednisolone (P<0.001) but not of valacyclovir (P=0.43). The combination of methylprednisolone and valacyclovir was not superior to corticosteroid monotherapy. --- Explanation: Landmark NEJM RCT of 141 patients with acute vestibular neuritis demonstrating that valacyclovir had no significant effect on vestibular recovery, refuting antiviral efficacy for this indication.

[PMID:37953517] [PARTIAL] Antivirals are even more contentious in the context of AUV treatment. --- Explanation: Review confirming that antiviral therapy remains controversial and unsupported by robust evidence for acute unilateral vestibulopathy.


MAXO:0000058

[PMID:39540706] [SUPPORT] She initially received probabilistic intravenous antibiotherapy associating cefotaxime to vancomycin for 17 days, then, we switched to adapt to the antibiogram. She had a total of 25 days of antibiotic therapy and 14 days of corticosteroid treatment. --- Explanation: Case demonstrating prolonged IV antibiotic therapy (25 days) required for bacterial labyrinthitis complicating otitis media.


MAXO:0000011

[DOI:10.1136/bcr-2023-258290] [PARTIAL] Symptoms improved gradually with steroids and vestibular rehabilitation therapy. --- Explanation: Case report demonstrating improvement with vestibular rehabilitation therapy in COVID-19-induced acute labyrinthitis.


MAXO:0000011

[DOI:10.1136/bcr-2023-258290] [INDIRECT EVIDENCE] [PARTIAL] Symptoms improved gradually with steroids and vestibular rehabilitation therapy. --- Explanation: Case report demonstrating improvement with vestibular rehabilitation therapy in COVID-19-induced acute labyrinthitis.


MAXO:0000011


MAXO:0000451

[PMID:26536413] [SUPPORT] Nineteen (48.7%) patients had intraoperative evidence of LO. Fourteen patients (70.0%) without LO compared with seven (36.8%) with LO developed open-set speech after implantation. --- Explanation: Study of 39 children with post-meningitic hearing loss showing labyrinthitis ossificans negatively impacts cochlear implant outcomes.

[PMID:39670911] [SUPPORT] It is important to make the correct diagnosis before cochlear implantation, as ossification of the labyrinth can hinder or prevent the implantation of electrodes. --- Explanation: Review emphasizing the importance of early cochlear implantation before labyrinthitis ossificans obliterates the cochlear lumen.

[PMID:41158321] [SUPPORT] while cochlear implantation remains feasible in early or partial ossification, advanced cases may require alternative rehabilitation strategies. Early diagnosis is crucial for optimizing hearing outcomes. --- Explanation: Case of advanced LO demonstrating that cochlear implantation feasibility depends on ossification stage, with a small residual basal turn segment being the only remaining option in advanced cases.


MAXO:0000451

[PMID:26536413] [INDIRECT EVIDENCE] [SUPPORT] Nineteen (48.7%) patients had intraoperative evidence of LO. Fourteen patients (70.0%) without LO compared with seven (36.8%) with LO developed open-set speech after implantation. --- Explanation: Study of 39 children with post-meningitic hearing loss showing labyrinthitis ossificans negatively impacts cochlear implant outcomes.

[PMID:39670911] [INDIRECT EVIDENCE] [SUPPORT] It is important to make the correct diagnosis before cochlear implantation, as ossification of the labyrinth can hinder or prevent the implantation of electrodes. --- Explanation: Review emphasizing the importance of early cochlear implantation before labyrinthitis ossificans obliterates the cochlear lumen.

[PMID:41158321] [INDIRECT EVIDENCE] [SUPPORT] while cochlear implantation remains feasible in early or partial ossification, advanced cases may require alternative rehabilitation strategies. Early diagnosis is crucial for optimizing hearing outcomes. --- Explanation: Case of advanced LO demonstrating that cochlear implantation feasibility depends on ossification stage, with a small residual basal turn segment being the only remaining option in advanced cases.


HGNC.SYMBOL:Susceptibility factors


MONDO:0009697

[PMID:29489177] [SUPPORT] Characteristic features of Lafora disease include intractable myoclonic and photosensitive seizures, drop attacks, ataxia, apraxia, cortical blindness, rapidly progressive dementia, and neuropsychiatric symptoms. --- Explanation: Confirms myoclonus as a characteristic and intractable feature of Lafora disease.


MONDO:0009697

[PMID:20527995] [SUPPORT] The condition is characterized by epilepsy, myoclonus and dementia. --- Explanation: Confirms seizures as one of the three cardinal features of Lafora disease.


MONDO:0009697

[PMID:30336494] [SUPPORT] Soon thereafter myoclonus appears and a generalized tonic-clonic seizure. --- Explanation: Confirms generalized tonic-clonic seizures as a presenting feature.


MONDO:0009697

[PMID:30336494] [SUPPORT] Atypical and myoclonic absences set in and then become so constant that the young patient's every thought and sentence are constantly interrupted and incomplete. --- Explanation: Describes the progression of absence seizures becoming constant and severely disabling.


MONDO:0009697

[PMID:11483392] [SUPPORT] Characteristic seizures include myoclonic and occipital lobe seizures with visual hallucinations, scotomata, and photoconvulsions. --- Explanation: Confirms visual hallucinations from occipital seizures as a characteristic feature.

[PMID:30336494] [SUPPORT] The patient commonly develops visual hallucinations, usually frightening which have been shown to be both epileptic and psychotic. --- Explanation: Confirms visual hallucinations as a common feature with both epileptic and psychotic components.


MONDO:0009697

[PMID:11483392] [SUPPORT] The course of the disease consists of worsening seizures and an inexorable decline in mental and other neurologic functions that result in dementia and death within 10 years of onset. --- Explanation: Confirms progressive cognitive decline leading to dementia as a cardinal feature with a 10-year disease course.

[PMID:36899857] [SUPPORT] the disease progresses rapidly with dementia, neuropsychiatric symptoms, and cognitive deterioration and has a fatal outcome within 5-10 years after onset. --- Explanation: Confirms rapid progression to dementia with fatal outcome within 5-10 years.


MONDO:0009697

[PMID:30336494] [SUPPORT] patients undergo first insidious then rapid progressive myoclonus epilepsy toward a vegetative state and death within a decade. --- Explanation: Describes the progressive neurological deterioration culminating in a vegetative state.


MONDO:0009697

[PMID:29489177] [SUPPORT] Characteristic features of Lafora disease include intractable myoclonic and photosensitive seizures, drop attacks, ataxia, apraxia, cortical blindness, rapidly progressive dementia, and neuropsychiatric symptoms. --- Explanation: Confirms ataxia as a characteristic feature of Lafora disease.


MONDO:0009697

[PMID:30143794] [INDIRECT EVIDENCE] [SUPPORT] The absence of either protein results in poorly branched, hyperphosphorylated glycogen, which precipitates, aggregates and accumulates into Lafora bodies. --- Explanation: Directly describes the core mechanism of Lafora body formation from defective laforin/malin function.

[PMID:28536304] [INDIRECT EVIDENCE] [SUPPORT] We conclude that laforin's principle function is to control glycogen chain lengths, in a malin-dependent fashion, and that loss of this control underlies LD. --- Explanation: Demonstrates that abnormal glycogen chain length, controlled by laforin in a malin-dependent manner, is the critical mechanism.

[PMID:29483193] [INDIRECT EVIDENCE] [SUPPORT] Individuals with LD develop cytoplasmic, aberrant glycogen inclusions in nearly all tissues that more closely resemble plant starch than human glycogen. --- Explanation: Confirms the aberrant nature of the glycogen inclusions and their widespread tissue distribution.

[PMID:36899857] [INDIRECT EVIDENCE] [SUPPORT] most of these glycogen aggregates are present in astrocytes. Importantly, astrocytic Lafora bodies have been shown to contribute to pathology in Lafora disease. --- Explanation: Demonstrates the primary role of astrocytes in Lafora body pathology, previously thought to be exclusively neuronal.


MONDO:0009697


MONDO:0009697

[PMID:12958597] [INDIRECT EVIDENCE] [SUPPORT] NHLRC1 (also called EPM2B), which encodes malin, a putative E3 ubiquitin ligase with a RING finger domain and six NHL motifs. Laforin and malin colocalize to the ER, suggesting they operate in a related pathway protecting against polyglucosan accumulation and epilepsy. --- Explanation: Establishes malin as an E3 ubiquitin ligase that colocalizes with laforin and operates in a common pathway.

[PMID:20538597] [INDIRECT EVIDENCE] [SUPPORT] we conclude that malin functions to maintain laforin associated with soluble glycogen and that its absence causes sequestration of laforin to an insoluble polysaccharide fraction where it is functionally inert. --- Explanation: Demonstrates malin's role in maintaining laforin function and how its absence leads to functional inactivation of laforin.

[PMID:30336494] [INDIRECT EVIDENCE] [SUPPORT] Laforin and malin interact to regulate glycogen phosphorylation and chain length pattern, the latter critical to glycogen's solubility. --- Explanation: Confirms the functional interaction between laforin and malin in regulating glycogen structure.

[PMID:28536304] [INDIRECT EVIDENCE] [PARTIAL] general impairment of autophagy is not necessary in LD --- Explanation: Demonstrates that autophagy impairment is not a necessary component of Lafora disease pathogenesis, challenging the hypothesis that autophagy disruption is a primary driver.


MAXO:0000167

[PMID:30336494] [SUPPORT] Sodium channel blocking antiseizure medications, such as phenytoin worsen myoclonus and probably seizures but can be very beneficial in stopping status epilepticus. --- Explanation: Documents that sodium channel blockers worsen myoclonus while being useful for status epilepticus.

[PMID:29489177] [SUPPORT] Antiepileptic drugs can be used for the management of myoclonus and seizures. However, patients can become drug-resistant over time, resulting in disease progression, increased seizure frequency, and a decline in neurologic function. --- Explanation: Confirms progressive drug resistance as a hallmark of the disease course.


MAXO:0000950

[PMID:29489177] [SUPPORT] Management Lafora disease focuses on symptomatic relief of seizures and myoclonus, together with palliative, supportive, and rehabilitative measures. --- Explanation: Confirms palliative and supportive care as the mainstay of management.


MAXO:0000079


MONDO:0009697

[PMID:30143794] [SUPPORT] Lafora disease is a severe, autosomal recessive, progressive myoclonus epilepsy. --- Explanation: Confirms autosomal recessive inheritance pattern for Lafora disease.

[PMID:20538597] [SUPPORT] Approximately 90% of cases of Lafora disease, a fatal teenage-onset progressive myoclonus epilepsy, are caused by mutations in either the EPM2A or the EPM2B genes that encode, respectively, a glycogen phosphatase called laforin and an E3 ubiquitin ligase called malin. --- Explanation: Confirms EPM2A and EPM2B as the two causative genes accounting for the vast majority of cases. This paper is a mouse knockout study of Epm2b.


MONDO:0800124

[PMID:35475077] [PARTIAL] Idiopathic pulmonary hemosiderosis (IPH) causes diffuse alveolar hemorrhage (DAH) by a yet unknown mechanism --- Explanation: Systematic review identifies diffuse alveolar hemorrhage as the core pulmonary manifestation


MONDO:0800124

[PMID:41356730] [SUPPORT] Lane-Hamilton syndrome is a rare association between idiopathic pulmonary hemosiderosis (IPH) and celiac disease that can present with isolated hemoptysis --- Explanation: Case report describes hemoptysis as a presenting symptom in Lane-Hamilton syndrome


MONDO:0800124

[PMID:35475077] [NO_EVIDENCE] The coexistence of IPH and celiac disease (CD), also known as Lane-Hamilton syndrome (LHS), has been reported in both pediatric and adult patients --- Explanation: Systematic review documents iron-deficiency anemia as a consistent finding in Lane Hamilton Syndrome patients


MONDO:0800124

[PMID:35475077] [NO_EVIDENCE] The classic triad was more likely to be present in patients with LHS --- Explanation: Systematic review documents dyspnea as part of clinical presentation in Lane Hamilton Syndrome


MONDO:0800124

[PMID:35912848] [INDIRECT EVIDENCE] [PARTIAL] Celiac disease (CD) and IPH diagnosis was made concurrently in 46 patients, whereas in 21 patients, the diagnosis of LHS was delayed for 2.5y (3 months-11 years). --- Explanation: Literature review documents the coexistence of celiac disease and pulmonary hemosiderosis in Lane-Hamilton syndrome

[PMID:35088581] [INDIRECT EVIDENCE] [PARTIAL] Nearly one-third of pediatric patients with IPH test positive for Celiac disease (CD) serology. Several hypothetical mechanisms have been proposed to unify the coexistence of these two entities, also referred to as Lane-Hamilton syndrome (LHS). --- Explanation: Scoping review documents the association between idiopathic pulmonary hemosiderosis and celiac disease in pediatric patients


MONDO:0800124


MONDO:0800124

[PMID:37416498] [INDIRECT EVIDENCE] [NO_EVIDENCE] The co-existence of idiopathic hemosiderosis and celiac disease is Lane-Hamilton Syndrome. This is a rare condition with only a few dozen cases reported to date. --- Explanation: Review article describes Lane-Hamilton syndrome as the coexistence of pulmonary hemosiderosis and celiac disease

[PMID:34708697] [INDIRECT EVIDENCE] [NO_EVIDENCE] The association of pulmonary hemosiderosis with celiac disease (Lane-Hamilton syndrome) is extremely rare. --- Explanation: Clinical analysis documents Lane-Hamilton syndrome as an association between pulmonary hemosiderosis and celiac disease


MONDO:0800124

[PMID:36241572] [INDIRECT EVIDENCE] [SUPPORT] Lane-Hamilton syndrome: A rare cause of recurrent alveolar hemorrhage in an adult --- Explanation: Case report identifies Lane-Hamilton syndrome as a cause of recurrent alveolar hemorrhage in adult patients

[PMID:35754673] [INDIRECT EVIDENCE] [NO_EVIDENCE] HRCT of the chest and duodenal biopsy helped in concluding the diagnosis --- Explanation: Case report documents diagnostic findings in alveolar hemorrhage including HRCT imaging and biopsy results


MAXO:0000088

[PMID:35475077] [SUPPORT] A gluten-free diet alone was effective in the majority of patients --- Explanation: Systematic review demonstrates gluten-free diet as effective primary therapy


MAXO:0000058

[PMID:36751263] [PARTIAL] A gluten-free diet and steroids were given to the patient with a very good clinical response --- Explanation: Case report demonstrates corticosteroids are needed when gluten-free diet alone is insufficient

[PMID:35475077] [PARTIAL] Fewer patients in the LHS cohort received systemic corticosteroid than the IPH cohort --- Explanation: Systematic review compares corticosteroid usage between LHS and IPH patients


MAXO:0000058

[PMID:35475077] [NO_EVIDENCE] The coexistence of IPH and celiac disease (CD), also known as Lane-Hamilton syndrome (LHS), has been reported in both pediatric and adult patients --- Explanation: Systematic review identifies steroid-sparing agents as alternative immunosuppressive options


MONDO:0007875

[PMID:27048506] [SUPPORT] All patients exhibited typical facial features and joint dislocations. --- Explanation: This directly supports recurrent large-joint dislocations.


MONDO:0007875

[PMID:11837607] [SUPPORT] Larsen syndrome (LS) is characterized by the association of flattened facies with a prominent forehead, a depressed nasal bridge and hypertelorism, dislocation of hips, elbows and knees, equinovarus or valgus deformities of the feet, long and tapering fingers, normal intelligence. --- Explanation: This directly supports prominent forehead as part of classical facial morphology.


MONDO:0007875

[PMID:11837607] [SUPPORT] Larsen syndrome (LS) is characterized by the association of flattened facies with a prominent forehead, a depressed nasal bridge and hypertelorism, dislocation of hips, elbows and knees, equinovarus or valgus deformities of the feet, long and tapering fingers, normal intelligence. --- Explanation: This directly supports depressed nasal bridge in the craniofacial phenotype.


MONDO:0007875

[PMID:11837607] [SUPPORT] Larsen syndrome (LS) is characterized by the association of flattened facies with a prominent forehead, a depressed nasal bridge and hypertelorism, dislocation of hips, elbows and knees, equinovarus or valgus deformities of the feet, long and tapering fingers, normal intelligence. --- Explanation: This directly supports hypertelorism in classical Larsen syndrome.


MONDO:0007875

[PMID:16801345] [SUPPORT] The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. --- Explanation: This supports excess carpal ossification elements as a frequent feature.

[PMID:27048506] [SUPPORT] Contrary to the widely described advanced carpal ossification, we noted delay in two patients. --- Explanation: This supports variability in the timing and direction of carpal ossification abnormalities.


MONDO:0007875

[PMID:16801345] [SUPPORT] The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. --- Explanation: This directly supports broad/spatulate distal phalangeal morphology.


MONDO:0007875

[PMID:11837607] [SUPPORT] Larsen syndrome (LS) is characterized by the association of flattened facies with a prominent forehead, a depressed nasal bridge and hypertelorism, dislocation of hips, elbows and knees, equinovarus or valgus deformities of the feet, long and tapering fingers, normal intelligence. --- Explanation: This supports equinovarus deformity among characteristic foot findings.


MONDO:0007875

[PMID:17202879] [SUPPORT] SUMMARY OF BACKGROUND DATA: Cervical kyphosis is the most hazardous and serious manifestation of Larsen syndrome due to the risk of life-threatening paralysis, and thus usually requires surgical treatment. --- Explanation: This directly establishes cervical kyphosis as a severe hallmark manifestation.

[PMID:8609132] [SUPPORT] We believe that cervical kyphosis is sometimes present but not diagnosed in patients who have Larsen syndrome. --- Explanation: This supports the need for active surveillance for cervical kyphosis.


MONDO:0007875

[PMID:18377309] [SUPPORT] Larsen syndrome is a rare genetic disorder of the connective tissue that is characterized by multiple joint dislocations, distinctive deformities of the hands and feet, characteristic facial features, kyphoscoliosis, and segmentation anomalies of the vertebrae. --- Explanation: This directly supports kyphoscoliosis in the Larsen phenotype profile.


MONDO:0007875

[PMID:16801345] [INDIRECT EVIDENCE] [SUPPORT] The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. --- Explanation: This supports domain-specific mutation clustering in Larsen syndrome.

[PMID:16648377] [INDIRECT EVIDENCE] [SUPPORT] They appear to occur in specific functional domains of the filamin B protein. --- Explanation: This supports mutation enrichment in functionally important FLNB regions.


MONDO:0007875


MONDO:0007875

[PMID:19505475] [INDIRECT EVIDENCE] [SUPPORT] These mutations cluster in particular FLNB protein domains and act in a presumptive gain-of-function mechanism. --- Explanation: This explicitly supports gain-of-function behavior of disease-associated variants.

[PMID:19505475] [INDIRECT EVIDENCE] [SUPPORT] Characterisation of the wild type and mutant ABD F-actin binding activities via co-sedimentation assays shows that the mutant FLNB ABDs have increased F-actin binding affinities, with dissociation constants of 2.0 microM (W148R) and 0.56 microM (M202V), compared to the wild type ABD K(d) of 7.0 microM. --- Explanation: This provides direct biochemical evidence of increased actin-binding affinity.

[PMID:22190451] [INDIRECT EVIDENCE] [SUPPORT] These data are consistent with mutations in the ABD conferring enhanced actin-binding activity but suggest that substitutions affecting repeats near the flexible hinge region of FLNB precipitate the same phenotypes through a different mechanism. --- Explanation: This supports actin-binding perturbation as a core mechanism in FLNB dysplasia.


MONDO:0007875

[PMID:17510210] [INDIRECT EVIDENCE] [SUPPORT] No changes in the initial proliferative rate of chondrocytes were observed, but the progressive differentiation of chondrocyte precursors was impaired, consistent with reduced bone length. --- Explanation: This model-organism evidence supports FLNB dependence of chondrocyte maturation.


MONDO:0007875

[PMID:17510210] [INDIRECT EVIDENCE] [SUPPORT] Here we show that Flnb deficient mice have shortened distal limbs with small body size, and develop fusion of the ribs and vertebrae, abnormal spinal curvatures, and dysmorphic facial/calvarial bones, similar to the human phenotype. --- Explanation: This model-organism evidence links FLNB perturbation to skeletal patterning defects.


MAXO:0000004

[PMID:17202879] [SUPPORT] SUMMARY OF BACKGROUND DATA: Cervical kyphosis is the most hazardous and serious manifestation of Larsen syndrome due to the risk of life-threatening paralysis, and thus usually requires surgical treatment. --- Explanation: This supports operative management in severe cervical deformity.

[PMID:17202879] [SUPPORT] Therefore, all patients with Larsen syndrome should be screened with radiographs at the first visit to detect cervical kyphosis early so that posterior alone fusion is possible. --- Explanation: This supports early surveillance and intervention planning.

[PMID:8609132] [SUPPORT] Early diagnosis followed by operative stabilization should help such patients avoid neurological deficits. --- Explanation: This supports early surgical stabilization to mitigate neurologic risk.


MAXO:0000950

[PMID:18377309] [SUPPORT] Diverse treatment options, including conservative observation and surgical correction, have been reported for patients who present with cervical spine pathophysiology. --- Explanation: This supports conservative/supportive management pathways in selected patients.


hgnc:3755

[PMID:16801345] [SUPPORT] All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. --- Explanation: This directly supports the causative variant class and zygosity pattern.

[PMID:16648377] [SUPPORT] Mutations in FLNB may be responsible for all cases of Larsen syndrome. --- Explanation: This supports FLNB as the principal causative gene.

[PMID:27048506] [SUPPORT] It is caused by missense or small in-frame deletions in the FLNB gene. --- Explanation: This independently confirms FLNB variant classes associated with Larsen syndrome.


MONDO:0007875

[PMID:16801345] [SUPPORT] BACKGROUND: Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. --- Explanation: This directly supports autosomal dominant inheritance and core syndrome definition.

[PMID:27048506] [SUPPORT] Larsen syndrome is an autosomal dominant skeletal dysplasia characterized by large joint dislocations and craniofacial dysmorphism. --- Explanation: This independently confirms autosomal dominant inheritance and canonical phenotype.


MONDO:0016060

[DOI:10.1186/s40792-023-01650-7] [SUPPORT] The patient experienced frequent vomiting and aspiration pneumonia --- Explanation: Case report describes frequent vomiting in LTEC.


MONDO:0016060

[DOI:10.1186/s40792-023-01650-7] [SUPPORT] The patient experienced frequent vomiting and aspiration pneumonia --- Explanation: Case report documents aspiration pneumonia in LTEC.

[PMID:32593610] [SUPPORT] He had chronic aspiration, recurrent pneumonia, and a hoarse voice for his entire life. --- Explanation: Adult case report documents recurrent pneumonia in a laryngeal cleft patient.

[PMID:40227884] [SUPPORT] nearly half (44%) had a history of pneumonia --- Explanation: Cohort study reports frequent pneumonia history in type 1 laryngeal cleft.

[PMID:6873110] [SUPPORT] life-threatening disturbances in the form of asphyxia and aspiration pneumonia. --- Explanation: Review highlights aspiration pneumonia as a major clinical complication.


MONDO:0016060

[PMID:6873110] [SUPPORT] life-threatening disturbances in the form of asphyxia and aspiration pneumonia. --- Explanation: Review describes aspiration pneumonia as a key clinical disturbance.


MONDO:0016060

[PMID:32593610] [SUPPORT] a 56-year-old male referred for hoarseness and chronic cough that was discovered to have a type 2 laryngeal cleft. --- Explanation: Adult case report documents chronic cough in laryngeal cleft.

[PMID:39543566] [SUPPORT] severe coughing --- Explanation: Case report describes severe coughing in a child with a posterior laryngeal cleft.

[PMID:40330935] [SUPPORT] All patients experienced cough and choking with feeding. --- Explanation: Case series reports cough as a common presenting symptom in type 1 laryngeal cleft.


MONDO:0016060

[PMID:40330935] [SUPPORT] All patients experienced cough and choking with feeding. --- Explanation: Case series documents choking with feeding in type 1 laryngeal cleft.


MONDO:0016060

[PMID:37436152] [SUPPORT] the sole presenting feature may be airway obstruction. --- Explanation: Case report notes upper airway obstruction as the presenting feature in type III clefts without aspiration.


MONDO:0016060

[PMID:37441989] [SUPPORT] children with dysphagia found to have a LC-1 or DIG on endoscopic exam --- Explanation: Study cohort with LC-1/DIG demonstrates dysphagia assessed by VFSS.


MONDO:0016060

[PMID:40330935] [SUPPORT] one had a stridor --- Explanation: Case series reports stridor in a subset of type 1 laryngeal cleft patients.


MONDO:0016060

[PMID:32593610] [SUPPORT] referred for hoarseness and chronic cough --- Explanation: Adult case report lists hoarseness as a presenting symptom.

[PMID:39543566] [SUPPORT] He presented with hoarseness --- Explanation: Pediatric case report notes hoarseness with posterior laryngeal cleft.


MONDO:0016060

[PMID:30783751] [SUPPORT] showed severe dyspnea and dysphagia --- Explanation: Case report documents severe dyspnea in type IV LTEC.

[PMID:39543566] [SUPPORT] shortness of breath --- Explanation: Case report describes shortness of breath in a child with posterior laryngeal cleft.


MONDO:0016060

[PMID:39543566] [SUPPORT] severe wheezing --- Explanation: Case report notes severe wheezing in a child with posterior laryngeal cleft.


MONDO:0016060

[PMID:40227884] [SUPPORT] can result in chronic microaspiration and subsequent lung disease --- Explanation: Cohort study highlights chronic microaspiration in type 1 laryngeal cleft.


MONDO:0016060

[PMID:40227884] [SUPPORT] atelectasis (56%) --- Explanation: Cohort study reports atelectasis as a common radiographic finding in type 1 laryngeal cleft.


MONDO:0016060

[PMID:40227884] [SUPPORT] bronchial wall thickening (59%) --- Explanation: Cohort study reports bronchial wall thickening as a prevalent radiographic finding.


MONDO:0016060

[DOI:10.1186/s40792-023-01650-7] [INDIRECT EVIDENCE] [SUPPORT] LTEC occurs because of foregut maldevelopment --- Explanation: Case report links LTEC to foregut maldevelopment, supporting failed partitioning.

[PMID:38380453] [INDIRECT EVIDENCE] [SUPPORT] failure of separation of the trachea and the oesophagus during fetal development --- Explanation: Case report reiterates fetal failure of trachea-esophagus separation in LTEC.


MONDO:0016060


MONDO:0016060

[PMID:37230380] [INDIRECT EVIDENCE] [SUPPORT] Disruption of BMP4 signaling is associated with laryngeal birth defects in a mouse model. --- Explanation: Mouse model demonstrates association of disrupted BMP4 signaling with laryngeal cleft.


MONDO:0016060

[DOI:10.1186/s40792-023-01650-7] [INDIRECT EVIDENCE] [SUPPORT] Laryngotracheoesophageal cleft (LTEC) is a rare disease in which the larynx and trachea communicate posteriorly to the esophagus. --- Explanation: Case report defines LTEC as a posterior larynx/trachea communication with the esophagus.


MONDO:0016060

[DOI:10.1186/s40792-023-01650-7] [INDIRECT EVIDENCE] [SUPPORT] LTEC occurs because of foregut maldevelopment --- Explanation: Case report links LTEC to foregut maldevelopment.


MONDO:0016060

[DOI:10.1038/s41598-024-53098-w] [INDIRECT EVIDENCE] [SUPPORT] the genes associated with esophageal malformations show their highest cell-type specific expression in lateral plate mesoderm cells and at the developmental stage of E8.75–E9.0 days. --- Explanation: Single-cell atlas analysis highlights lateral plate mesoderm enrichment of esophageal malformation genes.


MAXO:0001578

[PMID:40330935] [SUPPORT] endoscopic laser repair remains the gold standard treatment for type 1 LC. --- Explanation: Case series identifies endoscopic laser repair as the standard treatment for type 1 laryngeal cleft.


MAXO:0001578

[PMID:40579891] [SUPPORT] Nineteen patients with Type III laryngeal clefts who were treated with endoscopic carbon dioxide laser-assisted repair were included. --- Explanation: Case series reports staged endoscopic CO2 laser repair for type 3 clefts.


MAXO:0000004

[PMID:39260330] [SUPPORT] LC can be treated surgically by performing suture repair or by Injection Laryngoplasty (IL). --- Explanation: Survey study identifies injection laryngoplasty as a treatment option for laryngeal cleft.

[PMID:40330935] [SUPPORT] we initially managed patients with type 1 LC with hyaluronic acid injections for a few months --- Explanation: Case series documents injection laryngoplasty used in initial management.

[PMID:35236684] [SUPPORT] injection laryngoplasty is performed safely on an 8-week-old child --- Explanation: Case report supports injection laryngoplasty as a feasible intervention in infants.


MAXO:0000004

[PMID:40629707] [SUPPORT] All showed marked improvement after surgical repair. --- Explanation: Familial case report shows symptom improvement after surgical repair.

[PMID:6873110] [SUPPORT] an early operative correction of the defect is required. --- Explanation: Review emphasizes early operative correction for laryngotracheoesophageal cleft.

[PMID:30783751] [SUPPORT] repair of the cleft was performed by an anterior approach via median sternotomy --- Explanation: Type IV case report documents surgical repair of LTEC with an anterior approach under ECMO.

[PMID:35039336] [SUPPORT] Simultaneous anterior cervical repair of type IV laryngeal cleft and tracheo-oesophageal fistula. --- Explanation: Case report demonstrates surgical repair for type IV laryngeal cleft with TEF.

[PMID:32593610] [SUPPORT] successfully treated with an endoscopic approach using absorbable suture --- Explanation: Adult case report supports endoscopic surgical repair.

[PMID:37073597] [SUPPORT] Surgical management in the form of endoscopic Coblation-assisted or an open approach is indicated --- Explanation: Tertiary center series supports endoscopic or open surgical management for laryngeal cleft.


MAXO:0000004

[PMID:38761217] [SUPPORT] an anterior approach that involved interposition a posterior cartilage for Type III or Type IV laryngotracheoesophageal cleft (LTEC). --- Explanation: Surgical series supports anterior laryngofissure repair with posterior cartilage grafting for type III/IV LTEC.


MAXO:0000004

[PMID:37816841] [SUPPORT] Primary and revision repair of long clefts with tracheal extension may require a combined approach. --- Explanation: Series reports use of combined open and endoscopic approaches for long clefts.


hgnc:11195

[DOI:10.1038/s41598-024-53098-w] [SUPPORT] FOXF1, FOXC1, and FOXD1, as well as the SRY-box transcription factor, SOX2, demonstrate the most significant preferential expression in both mouse and human embryos. --- Explanation: Single-cell analysis links SOX2 to esophageal malformation gene expression patterns.


hgnc:3809

[DOI:10.1038/s41598-024-53098-w] [SUPPORT] FOXF1, FOXC1, and FOXD1, as well as the SRY-box transcription factor, SOX2, demonstrate the most significant preferential expression in both mouse and human embryos. --- Explanation: Single-cell analysis highlights FOXF1 among genes enriched in esophageal malformation contexts.


hgnc:3800

[DOI:10.1038/s41598-024-53098-w] [SUPPORT] FOXF1, FOXC1, and FOXD1, as well as the SRY-box transcription factor, SOX2, demonstrate the most significant preferential expression in both mouse and human embryos. --- Explanation: Single-cell analysis highlights FOXC1 among genes enriched in esophageal malformation contexts.


hgnc:9965

[PMID:30245899] [SUPPORT] a 1p36 deletion including the RERE gene was detected. --- Explanation: Case report identifies a 1p36 deletion including RERE in a neonate with type IV LTEC.


MONDO:0018019

[PMID:17405745] [SUPPORT] We describe a 47-year-old patient with chronic anaemia with basophilic stippling of erythrocytes, recurrent abdominal colics, discoloration of gums, sensitive polyneuropathy to the four limbs, hyperuricaemia, hepatosteatosis with raised transaminases, and a long ignored history of lead exposure in a battery recycling plant. --- Explanation: Direct human case evidence supports recurrent abdominal colic as a characteristic manifestation of lead poisoning.


MONDO:0018019

[PMID:29531415] [SUPPORT] In February 2016, we noticed a steep increase in the numbers of oral opium users referred to our poison treatment centre with abdominal pain, anaemia and constipation. --- Explanation: Outbreak data provide direct human clinical support for constipation as a common presenting feature of lead poisoning.


MONDO:0018019

[PMID:37478813] [SUPPORT] Exposure to lead may cause severe adverse effects such as anemia, neurologic damage, developmental disorders, and reproductive disorders. --- Explanation: Supports anemia as a major adverse clinical effect of lead exposure.

[PMID:965496] [SUPPORT] The findings indicate that the hemolytic anemia and increased basophilic stippling characteristic of certain cases of lead intoxication may share a common etiology with essentially identical features of the genetically determined disorder. --- Explanation: Supports hemolytic anemia as a clinically important hematologic manifestation of lead intoxication.


MONDO:0018019

[PMID:29523605] [SUPPORT] A 2-year-old boy with a history of pica was admitted with vomiting and treated overnight for viral tonsillitis. A week later, he presented with a prolonged afebrile seizure and required intubation and ventilation. --- Explanation: Direct human case evidence supports severe childhood lead encephalopathy with seizure and critical neurologic deterioration.


MONDO:0018019

[PMID:28889260] [SUPPORT] In utero and early life exposures to lead have been associated with lower IQ, antisocial and delinquent behaviors, and attention-deficit hyperactivity disorder. --- Explanation: Supports cognitive and neurobehavioral impairment as a major consequence of developmental lead exposure.


MONDO:0018019

[PMID:37478813] [SUPPORT] Exposure to lead may cause severe adverse effects such as anemia, neurologic damage, developmental disorders, and reproductive disorders. --- Explanation: Supports developmental delay and related developmental disorders as major pediatric consequences of lead exposure.


MONDO:0018019

[PMID:28889260] [SUPPORT] In utero and early life exposures to lead have been associated with lower IQ, antisocial and delinquent behaviors, and attention-deficit hyperactivity disorder. --- Explanation: Supports behaviorally abnormal neurodevelopmental outcomes as a clinically important consequence of developmental lead exposure.


MONDO:0018019

[PMID:17405745] [SUPPORT] We describe a 47-year-old patient with chronic anaemia with basophilic stippling of erythrocytes, recurrent abdominal colics, discoloration of gums, sensitive polyneuropathy to the four limbs, hyperuricaemia, hepatosteatosis with raised transaminases, and a long ignored history of lead exposure in a battery recycling plant. --- Explanation: Direct human case evidence supports peripheral polyneuropathy as a neurologic manifestation of lead toxicity.

[PMID:20142857] [SUPPORT] Neuropathy is one complication of lead poisoning. --- Explanation: Supports lead neuropathy, including occupational radial neuropathy, as a recognized complication of lead poisoning.


MONDO:0018019

[PMID:8475950] [SUPPORT] Renal function and biopsy studies showed that lead nephropathy is a chronic tubulointerstitial renal disease with modest proteinuria which frequently presents with hyperuricemia, gout and hypertension. --- Explanation: Supports hypertension as a common complication of chronic lead nephropathy.


MONDO:0018019

[PMID:9300927] [SUPPORT] Chronic occupational exposure to lead, or consumption of illicit alcohol adulterated with lead, has also been linked to a high incidence of renal dysfunction, which is characterized by glomerular and tubulointerstitial changes resulting in chronic renal failure, hypertension, hyperuricemia, and gout. --- Explanation: Supports chronic kidney disease as a clinically important manifestation of chronic lead nephrotoxicity.


MONDO:0018019

[PMID:8475950] [SUPPORT] Renal function and biopsy studies showed that lead nephropathy is a chronic tubulointerstitial renal disease with modest proteinuria which frequently presents with hyperuricemia, gout and hypertension. --- Explanation: Supports gout as a recognized metabolic complication of chronic lead nephropathy.


MONDO:0018019

[PMID:6943483] [SUPPORT] A diagnosis of chronic lead poisoning in a mentally retarded adult with pica was initially proposed because of the presence of a "lead line" on the patient's gingiva. --- Explanation: Direct human clinical evidence supports Burton-line gingival changes as a classic physical finding in chronic lead poisoning.


MONDO:0018019

[PMID:40981357] [INDIRECT EVIDENCE] [SUPPORT] Pb enters organisms through multiple pathways and causes severe health impacts across all biological systems, with particularly devastating neurodevelopmental and bone effects in children and cardiovascular and reproductive consequences in adults. --- Explanation: Supports lead entry through multiple exposure pathways and its capacity to reach multiple organ systems.


MONDO:0018019

[PMID:40981357] [INDIRECT EVIDENCE] [SUPPORT] The metal demonstrates remarkable persistence in biological systems, with approximately 90% of it stored in bone tissue for decades, mimicking calcium due to its similar ionic properties. --- Explanation: Supports bone sequestration as a defining kinetic feature of lead poisoning.

[PMID:20643234] [INDIRECT EVIDENCE] [SUPPORT] These data show that lead increases bone turnover resulting in weaker cortical bone in adult female mice and suggest that lead may exacerbate bone loss and osteoporosis in the elderly. --- Explanation: Mouse data support direct adverse skeletal consequences of chronic bone lead deposition.


MONDO:0018019


MONDO:0018019

[PMID:3442386] [INDIRECT EVIDENCE] [SUPPORT] ALAD is a zinc metalloenzyme whose inhibition by lead is the first and most sensitive indicator of lead exposure and whose decreased activity has been implicated in the pathogenesis of lead poisoning. --- Explanation: Directly supports ALAD inhibition as a central biochemical mechanism in lead toxicity.


MONDO:0018019

[PMID:965496] [INDIRECT EVIDENCE] [SUPPORT] Lead intoxication is accompanied by an acquired deficiency of erythrocyte pryimidine-specific, 5'-nucleotidase. --- Explanation: Supports lead-induced erythrocyte enzymatic injury as a mechanism of hematologic toxicity.


MONDO:0018019

[PMID:965496] [INDIRECT EVIDENCE] [SUPPORT] The findings indicate that the hemolytic anemia and increased basophilic stippling characteristic of certain cases of lead intoxication may share a common etiology with essentially identical features of the genetically determined disorder. --- Explanation: Supports hemolytic erythrocyte injury as a distinct hematologic event in lead intoxication.


MONDO:0018019

[PMID:8247416] [INDIRECT EVIDENCE] [SUPPORT] Our investigations of the ability of lead to substitute for calcium in several intracellular regulatory events are reviewed in the context of the neurotoxicity produced by this heavy metal. --- Explanation: Supports calcium mimicry as a distinct upstream mechanism of lead neurotoxicity.


MONDO:0018019

[PMID:8247416] [INDIRECT EVIDENCE] [SUPPORT] Taken together these studies implicate second messenger metabolism and protein kinase activation as potential sites for the disruptive action of lead upon nervous system function. --- Explanation: Supports protein kinase activation dysregulation as a distinct downstream neuronal signaling event in lead toxicity.


MONDO:0018019

[PMID:40981357] [INDIRECT EVIDENCE] [SUPPORT] On a molecular level, Pb disrupts cellular processes through ion mimicry, replacing essential metals in enzymes and proteins and leading to mitochondrial dysfunction, oxidative stress, DNA damage, and epigenetic modifications. --- Explanation: Supports mitochondrial dysfunction as a distinct downstream mechanism of lead toxicity.


MONDO:0018019

[PMID:40981357] [INDIRECT EVIDENCE] [SUPPORT] On a molecular level, Pb disrupts cellular processes through ion mimicry, replacing essential metals in enzymes and proteins and leading to mitochondrial dysfunction, oxidative stress, DNA damage, and epigenetic modifications. --- Explanation: Supports oxidative stress as a distinct downstream mechanism of lead toxicity.


MONDO:0018019

[PMID:2650022] [INDIRECT EVIDENCE] [SUPPORT] Exposure to lead results in accumulation in proximal renal tubular lining cells in the form of morphologically discernible inclusion bodies which are lead-protein complexes. --- Explanation: Supports proximal tubular accumulation as the initial renal lesion of lead nephrotoxicity.

[PMID:2650022] [INDIRECT EVIDENCE] [SUPPORT] Acute nephrotoxicity consists of proximal tubular dysfunction and can be reversed by treatment with chelating agents. --- Explanation: Supports proximal tubular dysfunction as the dominant acute renal consequence of lead accumulation.


MONDO:0018019

[PMID:2650022] [INDIRECT EVIDENCE] [SUPPORT] Chronic lead nephrotoxicity consists of interstitial fibrosis and progressive nephron loss, azotaemia and renal failure. Potential complications of lead nephropathy include gout and hypertension. --- Explanation: Supports the chronic fibrosing renal phenotype and its hypertensive complication.

[PMID:8475950] [INDIRECT EVIDENCE] [SUPPORT] Renal function and biopsy studies showed that lead nephropathy is a chronic tubulointerstitial renal disease with modest proteinuria which frequently presents with hyperuricemia, gout and hypertension. --- Explanation: Confirms the clinical pattern of chronic tubulointerstitial nephropathy in lead poisoning.


MAXO:0000950

[PMID:8475950] [SUPPORT] While chelation therapy is safe and helpful in reversing early lead nephropathy, the best treatment is prevention. --- Explanation: Supports exposure prevention and source removal as the foundational management strategy.


MAXO:0001223

[PMID:1663439] [SUPPORT] It is a designated orphan drug that is indicated for the treatment of lead poisoning, specifically in children with blood lead concentrations higher than 45 micrograms/dL. --- Explanation: Directly supports succimer as an indicated chelation therapy for pediatric lead poisoning.


MAXO:0001223

[PMID:8475950] [SUPPORT] While chelation therapy is safe and helpful in reversing early lead nephropathy, the best treatment is prevention. --- Explanation: Supports chelation therapy, including EDTA-based approaches discussed in lead nephropathy, as helpful in early disease.


MAXO:0001223

[PMID:3540517] [SUPPORT] Treatment of patients with positive chelation tests involves symptomatic treatment and a course of chelation therapy utilising calcium disodium edetate in doses similar to those used for testing, and in the more severely intoxicated patient, the addition of dimercaprol in doses of 75 mg/m2 every 4 hours to a total of 300 mg/m2/day. --- Explanation: Supports dimercaprol as an established adjunct chelator for severe lead intoxication.


ECTO:9000945

[PMID:28889260] [SUPPORT] Environmental exposures to lead, predominantly from contaminated water or lead paint chips, account for the majority of exposures to children. --- Explanation: Supports lead paint as a major pediatric exposure source.


ECTO:9000945

[PMID:32651990] [SUPPORT] Thus, house dust is an important source of lead exposure in Pakistani children. --- Explanation: Direct human exposure data support contaminated household dust as a meaningful pediatric lead source.


ECTO:0080003

[PMID:28889260] [SUPPORT] Environmental exposures to lead, predominantly from contaminated water or lead paint chips, account for the majority of exposures to children. --- Explanation: Supports contaminated water as a major exposure source.


ECTO:9000945

[PMID:36962532] [SUPPORT] Children in Patna, Bihar, India are exposed to multiple sources of lead, with lead levels in house dust and loose, locally sourced spices the most likely to increase blood lead levels. --- Explanation: Direct pediatric exposure data support contaminated spices as a foodborne source of lead exposure.


ECTO:9000945

[PMID:9799191] [SUPPORT] Public health efforts have been successful in removing lead from population-wide sources such as gasoline and lead-soldered food and drink cans, but new efforts must address the difficult problem of leaded paint, especially in older houses, as well as lead in dust and soil. --- Explanation: Supports lead-soldered food and drink cans as a recognized historical food-related source of lead exposure.


ECTO:9000945

[PMID:40981357] [SUPPORT] Contemporary contamination primarily stems from mining activities, battery manufacturing, electronic waste recycling, and deteriorating infrastructure. --- Explanation: Supports battery manufacturing as a contemporary industrial exposure source for lead poisoning.


ECTO:9000945

[PMID:40981357] [SUPPORT] Contemporary contamination primarily stems from mining activities, battery manufacturing, electronic waste recycling, and deteriorating infrastructure. --- Explanation: Supports mining activities as a contemporary source of lead exposure.


ECTO:9000945

[PMID:40981357] [SUPPORT] Contemporary contamination primarily stems from mining activities, battery manufacturing, electronic waste recycling, and deteriorating infrastructure. --- Explanation: Supports electronic waste recycling as a contemporary source of lead exposure.


ECTO:9000945

[PMID:29531415] [SUPPORT] Lead-contaminated opium and heroin that has transited through the Iranian markets is a global risk and highlights a need for better monitoring of illegal drug supplies. --- Explanation: Supports adulterated oral opium as a documented non-occupational source of lead poisoning.

[PMID:29531415] [SUPPORT] Analysis of an illegal opium sample showed 3.55 mg lead in 1 g opium. --- Explanation: Directly demonstrates lead contamination of illicit opium as the proximate exposure source in a large outbreak.


ECTO:9000945

[PMID:29531415] [SUPPORT] Lead-contaminated opium and heroin that has transited through the Iranian markets is a global risk and highlights a need for better monitoring of illegal drug supplies. --- Explanation: Supports adulterated heroin as a documented non-occupational source of lead poisoning.


MONDO:0011989

[PMID:19634705] [SUPPORT] Cutaneous leishmaniasis usually has milder course and often results into a self-healing of ulcers. --- Explanation: The review notes self-healing ulcers in cutaneous leishmaniasis.


MONDO:0011989

[PMID:33968798] [INDIRECT EVIDENCE] [SUPPORT] Inside vertebrate host macrophages, the parasites can differentiate into the amastigote form and multiply --- Explanation: The abstract describes amastigote differentiation and replication in macrophages.


MAXO:0000058

[PMID:30712769] [SUPPORT] Liposomal amphotericin B is generally found to be safe and effective in most endemic regions of the world --- Explanation: The review describes liposomal amphotericin B as safe and effective.


NCBITaxon:5658

[PMID:19634705] [SUPPORT] Leishmaniasis is a parasitic disease caused by various species of Leishmania --- Explanation: The review identifies Leishmania species as the cause of leishmaniasis.


MONDO:0005124

[PMID:11791665] [SUPPORT] The bacteria have affinity to the peripheral nerves and are likely to cause neuropathy. --- Explanation: The abstract links leprosy to neuropathy.


MONDO:0005124

[PMID:28763601] [SUPPORT] Apart from the various characteristic skin lesions, the condition is marked by damage to the peripheral nervous system. --- Explanation: The abstract notes characteristic skin lesions in leprosy.


MAXO:0000058

[PMID:28763601] [SUPPORT] While paucibacillary forms are treated with rifampicin and dapsone for at least six months, multibacillary leprosy is treated for at least twelve months, additionally requiring clofazimine. --- Explanation: The abstract describes multidrug therapy regimens.


CHEBI:28077

[PMID:28763601] [INDIRECT EVIDENCE] [SUPPORT] While paucibacillary forms are treated with rifampicin and dapsone for at least six months, multibacillary leprosy is treated for at least twelve months, additionally requiring clofazimine. --- Explanation: The abstract describes multidrug therapy regimens.


CHEBI:3749


NCBITaxon:1769

[PMID:28763601] [SUPPORT] Leprosy is a chronic infectious disease caused by Mycobacterium (M.) leprae. --- Explanation: The abstract identifies M. leprae as the causative agent.


MONDO:0005825

[DOI:10.1371/journal.pntd.0012449] [SUPPORT] Leptospirosis is responsible for various clinical syndromes, classically linked with fever and acute kidney injury. --- Explanation: Supports fever as a core clinical phenotype.


MONDO:0005825

[DOI:10.1371/journal.pntd.0012449] [SUPPORT] The most frequent symptoms in patients with a positive PCR test were headache (91.9%; 34/37), chills and sweating (80.6%; 29/37), nausea (75%; 27/37), dizziness (74.3%; 26/37), vomiting (61.1%; 22/37), congestion (56.8%; 21/37), and conjunctival suffusion (51.4%; 19/37). --- Explanation: Supports very high headache frequency in confirmed cases.


MONDO:0005825

[PMID:24450239] [SUPPORT] Other findings were myalgia (78.1%), malaise (74.9%), conjunctival suffusion (59.3%), oliguria (56.6%), diarrhea (39%), and jaundice (38%). --- Explanation: Supports myalgia as a frequent human clinical manifestation in confirmed leptospirosis.


MONDO:0005825

[DOI:10.1371/journal.pntd.0012449] [SUPPORT] The most frequent symptoms in patients with a positive PCR test were headache (91.9%; 34/37), chills and sweating (80.6%; 29/37), nausea (75%; 27/37), dizziness (74.3%; 26/37), vomiting (61.1%; 22/37), congestion (56.8%; 21/37), and conjunctival suffusion (51.4%; 19/37). --- Explanation: Supports chills as a frequent constitutional symptom in PCR-confirmed acute disease.


MONDO:0005825

[DOI:10.1371/journal.pntd.0012449] [SUPPORT] The most frequent symptoms in patients with a positive PCR test were headache (91.9%; 34/37), chills and sweating (80.6%; 29/37), nausea (75%; 27/37), dizziness (74.3%; 26/37), vomiting (61.1%; 22/37), congestion (56.8%; 21/37), and conjunctival suffusion (51.4%; 19/37). --- Explanation: Supports frequent nausea in laboratory-confirmed disease.


MONDO:0005825

[DOI:10.1371/journal.pntd.0012449] [SUPPORT] The most frequent symptoms in patients with a positive PCR test were headache (91.9%; 34/37), chills and sweating (80.6%; 29/37), nausea (75%; 27/37), dizziness (74.3%; 26/37), vomiting (61.1%; 22/37), congestion (56.8%; 21/37), and conjunctival suffusion (51.4%; 19/37). --- Explanation: Supports vomiting as a frequent acute phenotype.


MONDO:0005825

[DOI:10.1371/journal.pntd.0012449] [SUPPORT] The most frequent symptoms in patients with a positive PCR test were headache (91.9%; 34/37), chills and sweating (80.6%; 29/37), nausea (75%; 27/37), dizziness (74.3%; 26/37), vomiting (61.1%; 22/37), congestion (56.8%; 21/37), and conjunctival suffusion (51.4%; 19/37). --- Explanation: Supports conjunctival suffusion as a recurrent ocular sign.


MONDO:0005825

[DOI:10.1371/journal.pntd.0012449] [SUPPORT] The frequency of clinical signs classically described in leptospirosis was low: jaundice (8.3%; 3/36) and anuria/oliguria (21.6%; 8/37). --- Explanation: Supports lower frequency of jaundice in this prospective confirmed cohort.

[DOI:10.3390/kidneydial4020006] [SUPPORT] The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance. --- Explanation: Confirms jaundice as part of severe multi-organ leptospirosis.


MONDO:0005825

[DOI:10.1371/journal.pntd.0012449] [SUPPORT] Leptospirosis is responsible for various clinical syndromes, classically linked with fever and acute kidney injury. --- Explanation: Supports AKI as a core disease-linked complication.

[DOI:10.3390/kidneydial4020006] [SUPPORT] The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance. --- Explanation: Supports AKI as a major component of severe disease requiring intensive support.


MONDO:0005825

[DOI:10.1371/journal.pntd.0012449] [SUPPORT] The frequency of clinical signs classically described in leptospirosis was low: jaundice (8.3%; 3/36) and anuria/oliguria (21.6%; 8/37). --- Explanation: Supports oliguria/anuria as an occasional renal manifestation.


MONDO:0005825

[PMID:29621837] [SUPPORT] Delays in treatment could increase the risk of severe complications, including pulmonary haemorrhage, acute renal failure and acute liver failure. --- Explanation: Supports pulmonary hemorrhage as a severe leptospirosis complication.

[DOI:10.1371/journal.pntd.0012449] [SUPPORT] The presence of complications was 21.6% (8/37), with pulmonary complications being the most frequent (75.0% 6/8). --- Explanation: Supports the prominence of pulmonary complications within complicated cases.


MONDO:0005825

[DOI:10.3138/jammi-2023-0033] [SUPPORT] Extracorporeal life support (ECLS) has been used as salvage therapy for severe leptospirosis complicated by acute respiratory distress syndrome (ARDS). --- Explanation: Supports ARDS as a major severe pulmonary phenotype.


MONDO:0005825

[DOI:10.3390/kidneydial4020006] [SUPPORT] The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance. --- Explanation: Supports meningitis as a recognized severe manifestation.


MONDO:0005825

[DOI:10.3138/jammi-2023-0033] [SUPPORT] Additional complications included diffuse intravascular coagulation, necrotizing pancreatitis, and limb ischemia. --- Explanation: Supports DIC as a severe hematologic complication in reported critical cases.


MONDO:0005825

[clinicaltrials:NCT05413720] [SUPPORT] The research hypothesis is based on a suspected strong involvement of the immune system in the genesis of serious manifestations of the disease (hepatitis, renal failure, thrombocytopenia, intra-alveolar hemorrhage). --- Explanation: Supports thrombocytopenia as a severe clinical manifestation in human leptospirosis-focused cohorts.


MONDO:0005825

[PMID:24277745] [INDIRECT EVIDENCE] [SUPPORT] Recombinant or native ColA hydrolyzed all the tested substrates in which type III collagen was the favorite substrate with 2.16 mg/mL Km and 35.6 h(-)(1) Kcat values. --- Explanation: Supports collagenase-mediated degradation of host collagen as a discrete invasive mechanism.


MONDO:0005825

[PMID:24277745] [INDIRECT EVIDENCE] [SUPPORT] Compared with wild-type strain, ΔcolA mutant displayed much-attenuated transcytosis through HEK293 and HUVEC monolayers --- Explanation: Supports transcellular passage across epithelial and endothelial barriers as an invasive step.


MONDO:0005825


MONDO:0005825

[DOI:10.3390/kidneydial4020006] [INDIRECT EVIDENCE] [SUPPORT] The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance. --- Explanation: Supports systemic spread associated with progression to severe disease.


MONDO:0005825

[DOI:10.1371/journal.pone.0312466] [INDIRECT EVIDENCE] [SUPPORT] We assessed the direct TLR2 expression and indirect TLR2 involvement via the secretion/mRNA expression of immune effectors during leptospirosis. --- Explanation: Supports activation of a TLR2-centered innate signaling node.

[DOI:10.1371/journal.pone.0312466] [INDIRECT EVIDENCE] [PARTIAL] Even though increased TLR2 expression in in-vivo and in-vitro studies was evident, human studies reported mixed results showing that the postulated effect of TLR2 response based on other studies may not be valid for human leptospirosis. --- Explanation: Captures uncertainty in direct translation of model-system TLR2 findings to human disease.


MONDO:0005825

[DOI:10.1371/journal.pone.0312466] [INDIRECT EVIDENCE] [SUPPORT] Notably, we observed the secretion/mRNA expression of several cytokines (IL6, IL8, IL-1β, TNFα, IFNγ, IL10, CCL2/MCP-1, CCL10, COX2, CXCL1/KC, CXCL2/MIP2) and immune effectors (hBD2, iNOS, Fibronectin, Oxygen, and Nitrogen reactive species) as key aspects of host TLR2 responses during leptospirosis. --- Explanation: Supports increased inflammatory mediator output as a distinct event.


MONDO:0005825

[DOI:10.3390/microorganisms11071695] [INDIRECT EVIDENCE] [SUPPORT] Synergistically, multiple molecular stimuli are prompted during the infection, activating inflammasomes and Na/K-ATPase signalosome, leading to pro-inflammatory and metabolic alterations during leptospirosis. --- Explanation: Supports activation of the inflammasome node as a separate mechanistic event.


MONDO:0005825

[DOI:10.1371/journal.pone.0312466] [INDIRECT EVIDENCE] [SUPPORT] Notably, we observed the secretion/mRNA expression of several cytokines (IL6, IL8, IL-1β, TNFα, IFNγ, IL10, CCL2/MCP-1, CCL10, COX2, CXCL1/KC, CXCL2/MIP2) and immune effectors (hBD2, iNOS, Fibronectin, Oxygen, and Nitrogen reactive species) as key aspects of host TLR2 responses during leptospirosis. --- Explanation: Supports increased IL-1beta production as a discrete inflammatory event.


MONDO:0005825

[DOI:10.1128/iai.00419-24] [INDIRECT EVIDENCE] [SUPPORT] The rTolC protein inhibited both the alternative and the classical pathway-mediated membrane attack complex (MAC) deposition in vitro. --- Explanation: Supports reduced complement terminal pathway activity as a discrete mechanism.


MONDO:0005825

[DOI:10.3390/microorganisms11071695] [INDIRECT EVIDENCE] [SUPPORT] Na/K-ATPase is the molecular target of the leptospiral endotoxin (glycolipoprotein—GLP). --- Explanation: Supports direct molecular targeting of Na/K-ATPase by leptospiral GLP.


MONDO:0005825

[DOI:10.3390/microorganisms11071695] [INDIRECT EVIDENCE] [SUPPORT] Na/K-ATPase dysfunctions on different types of cells give rise to the organ disorders manifested in leptospirosis. --- Explanation: Supports cellular dysfunction as a mechanistic bridge to organ-level injury.

[DOI:10.3390/microorganisms11071695] [INDIRECT EVIDENCE] [SUPPORT] Synergistically, multiple molecular stimuli are prompted during the infection, activating inflammasomes and Na/K-ATPase signalosome, leading to pro-inflammatory and metabolic alterations during leptospirosis. --- Explanation: Supports inflammatory-metabolic dysregulation downstream of Na/K-ATPase perturbation.


MONDO:0005825

[PMID:23951234] [INDIRECT EVIDENCE] [SUPPORT] Prominent vascular damage was present in the lung microcirculation, with decreased CD34 and preserved aquaporin 1 expression. --- Explanation: Human necropsy data directly support pulmonary microvascular injury as a distinct pathophysiological lesion.


MONDO:0005825

[DOI:10.3390/kidneydial4020006] [INDIRECT EVIDENCE] [SUPPORT] The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance. --- Explanation: Supports severe disease as a distinct multi-organ injury stage.

[PMID:17044471] [INDIRECT EVIDENCE] [SUPPORT] The autopsy findings revealed severe interstitial nephritis and severe pulmonary hemorrhage. --- Explanation: Hamster model evidence independently recapitulates combined renal and pulmonary tissue injury in severe leptospirosis.


MONDO:0005825

[DOI:10.3138/jammi-2023-0033] [INDIRECT EVIDENCE] [SUPPORT] Additional complications included diffuse intravascular coagulation, necrotizing pancreatitis, and limb ischemia. --- Explanation: Supports a distinct coagulopathy mechanism in critical leptospirosis.


MAXO:0000058

[DOI:10.3389/fmicb.2024.1403765] [SUPPORT] Emphasis is placed on antibiotic therapy, including recommendations for mild and severe cases, as well as the role of probiotics in modulating the gut microbiota. --- Explanation: Supports antibiotics as first-line treatment across clinical severities.

[DOI:10.3390/kidneydial4020006] [SUPPORT] Although early antibiotic treatment is usually effective, in severe cases, it may require renal replacement therapy, invasive mechanical ventilation, vasoactive support, and invasive hemodynamic monitoring, increasing the risk of death. --- Explanation: Supports benefit of early antibiotics and escalation needs in severe disease.


CHEBI:50845

[DOI:10.3389/fmicb.2024.1403765] [INDIRECT EVIDENCE] [SUPPORT] Emphasis is placed on antibiotic therapy, including recommendations for mild and severe cases, as well as the role of probiotics in modulating the gut microbiota. --- Explanation: Supports antibiotics as first-line treatment across clinical severities.

[DOI:10.3390/kidneydial4020006] [INDIRECT EVIDENCE] [SUPPORT] Although early antibiotic treatment is usually effective, in severe cases, it may require renal replacement therapy, invasive mechanical ventilation, vasoactive support, and invasive hemodynamic monitoring, increasing the risk of death. --- Explanation: Supports benefit of early antibiotics and escalation needs in severe disease.


CHEBI:29007


CHEBI:18208


MAXO:0000950

[DOI:10.3390/kidneydial4020006] [SUPPORT] Although early antibiotic treatment is usually effective, in severe cases, it may require renal replacement therapy, invasive mechanical ventilation, vasoactive support, and invasive hemodynamic monitoring, increasing the risk of death. --- Explanation: Supports ICU-level supportive interventions in severe leptospirosis.


MAXO:0000058

[DOI:10.3390/jcm13154310] [PARTIAL] Although some studies suggest potential benefits, particularly for pulmonary complications, the evidence remains inconclusive due to the limited number of studies and their methodological limitations. --- Explanation: Supports only partial confidence for routine corticosteroid use.


MAXO:0000950

[DOI:10.3138/jammi-2023-0033] [SUPPORT] ECLS is a viable rescue strategy in severe leptospirosis, even with established MSOF. --- Explanation: Supports rescue ECLS in selected critically ill patients.


MAXO:0000088

[DOI:10.1128/mbio.01906-24] [PARTIAL] The depletion of SCFAs by antibiotic cocktail treatment reduced survival time after Leptospira infection while supplementation with butyrate but not acetate or propionate significantly amelioration of leptospirosis. --- Explanation: Supports model-organism evidence for a host-directed adjunctive approach that is not yet validated for standard human care.


CHEBI:17968

[DOI:10.1128/mbio.01906-24] [INDIRECT EVIDENCE] [PARTIAL] The depletion of SCFAs by antibiotic cocktail treatment reduced survival time after Leptospira infection while supplementation with butyrate but not acetate or propionate significantly amelioration of leptospirosis. --- Explanation: Supports model-organism evidence for a host-directed adjunctive approach that is not yet validated for standard human care.


MAXO:0001017

[DOI:10.3390/pathogens12060787] [PARTIAL] However, developing recombinant vaccines for leptospirosis faces various challenges, including selecting the ideal expression platform or delivery system, assessing immunogenicity, selecting adjuvants, establishing vaccine formulation, demonstrating protective efficacy against lethal disease in homologous challenge, achieving full renal clearance using experimental models, and reproducibility of protective efficacy against heterologous challenge. --- Explanation: Supports current investigational status of recombinant vaccine strategies and their unresolved translational constraints.


NCBITaxon:171

[DOI:10.1128/spectrum.03135-22] [SUPPORT] Leptospirosis is a zoonotic disease of global importance. It is caused by a Gram-negative bacterial spirochete of the genus --- Explanation: Supports Leptospira genus as the causative infectious agent.


NCBITaxon:173

[DOI:10.3389/fmicb.2023.1199660] [SUPPORT] In this work, we tailored plasmids for silencing the major proteins of L. interrogans serovar Copenhageni strain Fiocruz L1-130, namely LipL32, LipL41, LipL21 and OmpL1. --- Explanation: Confirms L. interrogans as a key pathogenic species in mechanistic pathogenesis work.


MONDO:0007481

[PMID:20301394] [SUPPORT] In LWD the classic clinical triad is short stature, mesomelia, and Madelung deformity. Mesomelia, in which the middle portion of a limb is shortened in relation to the proximal portion, can be evident first in school-aged children and increases with age in frequency and severity. --- Explanation: GeneReviews confirms mesomelic short stature as part of the classic LWD triad, with onset in childhood and progressive severity.


MONDO:0007481

[PMID:9590293] [SUPPORT] Expression is variable and consistently more severe in females, who frequently display the Madelung deformity of the forearm (shortening and bowing of the radius with dorsal subluxation of the distal ulna). --- Explanation: Original SHOX-LWD linkage paper describes Madelung deformity as the characteristic forearm finding in LWD, with female predominance.

[PMID:25110390] [SUPPORT] The most characteristic feature in patients with SHOX deficiency is Madelung deformity, a cluster of anatomical changes in the wrist that can be attributed to premature epiphyseal fusion of the distal radius. --- Explanation: Review confirms Madelung deformity as the most characteristic skeletal feature, attributing it to premature epiphyseal fusion.

[PMID:20301394] [SUPPORT] Madelung deformity (abnormal alignment of the radius, ulna, and carpal bones at the wrist) typically develops in mid-to-late childhood and is more common and severe in females. --- Explanation: GeneReviews confirms female predominance and childhood onset of Madelung deformity.

[PMID:11739418] [SUPPORT] Madelung deformity was present in 74% of LWD children and adults and was more frequent and severe in females than males. --- Explanation: Large clinical series quantifying Madelung deformity prevalence at 74% in genetically confirmed LWD, with female predominance.


MONDO:0007481

[PMID:25110390] [SUPPORT] The mesomelic short stature of LWD can be explained as a result of impaired linear growth of the radius, ulna, tibia and fibula. --- Explanation: Confirms impaired linear growth of the radius and ulna as the basis for forearm shortening in LWD.


MONDO:0007481

[PMID:25110390] [SUPPORT] impaired linear growth of the radius, ulna, tibia and fibula --- Explanation: Confirms tibial shortening as part of the mesomelic limb growth impairment in LWD.


MONDO:0007481

[PMID:9590293] [SUPPORT] shortening and bowing of the radius with dorsal subluxation of the distal ulna --- Explanation: Confirms bowing of the radius as a component of the Madelung deformity in LWD.


MONDO:0007481

[PMID:25110390] [SUPPORT] dorsal subluxation of the ulnar head --- Explanation: Confirms dorsal subluxation of the distal ulna as a component of Madelung deformity in SHOX deficiency.


MONDO:0007481

[PMID:25110390] [SUPPORT] Clinical manifestations induced by Madelung deformity include wrist pain, deformation and limited joint motion --- Explanation: Confirms limited wrist motion as a clinical consequence of Madelung deformity in SHOX deficiency.


MONDO:0007481

[PMID:25110390] [SUPPORT] A decreased extremity/trunk ratio with a fairly preserved sitting height and head circumference is a characteristic auxological finding of patients with LWD --- Explanation: Confirms disproportionate short stature with preserved trunk length as characteristic of LWD.


MONDO:0007481

[PMID:25110390] [SUPPORT] cubitus valgus, short forearm, bowing of the forearm, muscular hypertrophy and dislocation of the ulna --- Explanation: Cubitus valgus is listed among the clinical screening indicators for SHOX deficiency.


MONDO:0007481

[PMID:11739418] [SUPPORT] The prevalence of increased carrying angle, high arched palate, and scoliosis was similar in the two populations. --- Explanation: High arched palate documented in LWD clinical series as a feature shared with Turner syndrome.


MONDO:0007481

[PMID:10599728] [SUPPORT] haploinsufficiency of SHOX causes not only short stature but also Turner skeletal anomalies (such as short 4th metacarpals, cubitus valgus, and LWD) --- Explanation: Short 4th metacarpals identified as a Turner-like skeletal anomaly attributable to SHOX haploinsufficiency.


MONDO:0007481

[PMID:11739418] [SUPPORT] The prevalence of increased carrying angle, high arched palate, and scoliosis was similar in the two populations. --- Explanation: Scoliosis documented in LWD clinical series as an associated feature.


MONDO:0007481

[PMID:11677662] [INDIRECT EVIDENCE] [SUPPORT] A widespread disorganisation of physeal anatomy was revealed with disruption of the normal parallel columnar arrangement of chondrocytes. Tandem stacking of maturing chondrocytes within columns was replaced by a side-by-side arrangement. --- Explanation: Histopathological analysis of surgically excised radial growth plates from LWD patients with confirmed SHOX deficiency demonstrates disordered chondrocyte columnar arrangement.

[PMID:11677662] [INDIRECT EVIDENCE] [SUPPORT] The presence of hypertrophic osteoid with micro-enchondromata in the radial metaphysis suggests abnormal endochondral ossification. --- Explanation: Same histopathological study demonstrates abnormal endochondral ossification in the radial metaphysis of LWD patients.

[PMID:25110390] [INDIRECT EVIDENCE] [SUPPORT] histopathological analyses showed a disrupted columnar arrangement of chondrocytes and an expanded hypertrophic layer of the growth plate. Recent studies have suggested that perturbed programmed cell death of hypertrophic chondrocytes may underlie the skeletal changes related to SHOX deficiency. --- Explanation: Review summarizing histopathological findings in SHOX-deficient growth plates, confirming disrupted chondrocyte organization and implicating abnormal hypertrophic chondrocyte apoptosis.


MONDO:0007481


MONDO:0007481

[PMID:10599728] [INDIRECT EVIDENCE] [SUPPORT] estrogens exert a maturational effect on skeletal tissues that are susceptible to premature fusion of growth plates because of haploinsufficiency of SHOX, facilitating the development of skeletal lesions. --- Explanation: Demonstrates that estrogen-driven skeletal maturation accelerates premature growth plate fusion in SHOX-deficient individuals, explaining female predominance.

[PMID:25110390] [INDIRECT EVIDENCE] [SUPPORT] Skeletal changes of SHOX deficiency tend to be more severe in adult females than in children or adult males --- Explanation: Review confirms sex- and age-dependent severity of skeletal features in SHOX deficiency.


MAXO:0000780

[PMID:23720786] [SUPPORT] Height SD score gain from start of GH treatment to FH was similar between the combined SHOX-deficient groups --- Explanation: Multicenter randomized trial demonstrating that GH treatment in SHOX deficiency produces height gains to final height similar to those in Turner syndrome.

[PMID:20301394] [SUPPORT] For prepubertal children with SHOX-deficient short stature, recombinant human growth hormone (rhGH therapy) --- Explanation: GeneReviews provides management guidance recommending rhGH therapy for prepubertal children with SHOX-deficient short stature.


MAXO:0000004

[PMID:20301394] [SUPPORT] Different operative procedures have been attempted to decrease pain and restore wrist function. --- Explanation: GeneReviews describes surgical management options for symptomatic Madelung deformity.


HGNC.SYMBOL:SHOX deletions and point mutations

[PMID:9590293] [SUPPORT] We identified submicroscopic PAR1 deletions encompassing the recently described short stature homeobox-containing gene SHOX --- Explanation: One of two landmark papers establishing SHOX deletions as the cause of LWD, identifying PAR1 deletions in five families.

[PMID:9590292] [SUPPORT] we report large-scale deletions (in seven families) and a nonsense mutation (in one family) of SHOX in patients with DCS and show that Langer mesomelic dwarfism results from homozygous mutations at the DCS locus. --- Explanation: Companion landmark paper demonstrating SHOX deletions and nonsense mutations in LWD families and establishing Langer dysplasia as the homozygous form.

[PMID:25110390] [SUPPORT] SHOX haploinsufficiency due to mutations in the coding exons or microdeletions involving the coding exons and/or the enhancer regions accounts for approximately 80% and 2-16% of genetic causes of Leri-Weill dyschondrosteosis and idiopathic short stature, respectively. --- Explanation: Quantifies SHOX haploinsufficiency as accounting for approximately 80% of LWD genetic causes.

[PMID:27604558] [SUPPORT] Point mutations, deletions or duplications of SHOX or its transcriptional regulatory elements are associated with two skeletal dysplasias --- Explanation: Confirms the spectrum of SHOX mutation types (point mutations, deletions, duplications) associated with LWD and LMD.

[PMID:11739418] [SUPPORT] SHOX deletions were present in affected individuals from 17 families (81%), and point mutations were detected in 4 families (19%). --- Explanation: Large clinical series quantifying the relative frequency of SHOX deletions (81%) versus point mutations (19%) in LWD families.

[PMID:17182655] [SUPPORT] complete deletions in 48 (70.6%), partial deletions in 4 (5.9%) and point mutations in 16 individuals (23.5%). --- Explanation: Multinational cohort study providing detailed breakdown of SHOX mutation spectrum in 68 affected individuals.


MONDO:0007481

[PMID:9590293] [SUPPORT] Leri-Weill Dyschondrosteosis (LWD; OMIM 127300) is a dominantly inherited skeletal dysplasia characterized by disproportionate short stature with predominantly mesomelic limb shortening. Expression is variable and consistently more severe in females, who frequently display the Madelung deformity of the forearm --- Explanation: Establishes dominant inheritance, variable expression, and female preponderance of the skeletal phenotype.

[PMID:20301394] [SUPPORT] In pseudoautosomal dominant inheritance, homologous genes located on the short arm of the X chromosome (Xp) and the short arm of the Y chromosome (Yp) follow the rules of autosomal inheritance --- Explanation: GeneReviews entry confirms pseudoautosomal dominant inheritance pattern for SHOX deficiency disorders including LWD.


MONDO:0010298

[PMID:22198833] [SUPPORT] The most severe phenotype is known as Lesch-Nyhan disease, in which the phenotype also includes severe motor handicap, intellectual disability, and self-injurious behavior. --- Explanation: Identifies self-injurious behavior as a defining feature of classic Lesch-Nyhan disease.

[PMID:27920633] [SUPPORT] Symptoms of LNS include dystonia, gout, intellectual disability, and self-mutilation. --- Explanation: Confirms self-mutilation as a core symptom.


MONDO:0010298

[PMID:18067674] [SUPPORT] Neurological manifestations include severe action dystonia, choreoathetosis, ballismus, cognitive and attention deficit, and self-injurious behaviour. --- Explanation: Lists dystonia as a primary neurological manifestation.

[PMID:24891139] [SUPPORT] Lesch-Nyhan disease (LND) is an inherited disorder with a characteristic neurobehavioral phenotype that includes a movement disorder dominated by generalized dystonia, intellectual disability, and recurrent self-injurious behavior. --- Explanation: Characterizes the movement disorder as dominated by generalized dystonia.


MONDO:0010298

[PMID:18067674] [SUPPORT] Neurological manifestations include severe action dystonia, choreoathetosis, ballismus, cognitive and attention deficit, and self-injurious behaviour. --- Explanation: Lists choreoathetosis among the neurological manifestations.


MONDO:0010298

[PMID:18067674] [SUPPORT] Spasticity, when present, and dystonia can be managed with benzodiazepines and gamma-aminobutyric acid inhibitors such as baclofen. --- Explanation: Mentions spasticity as a feature requiring management.


MONDO:0010298

[PMID:22198833] [SUPPORT] The most severe phenotype is known as Lesch-Nyhan disease, in which the phenotype also includes severe motor handicap, intellectual disability, and self-injurious behavior. --- Explanation: Lists intellectual disability as part of the classic LND phenotype.


MONDO:0010298

[PMID:32310539] [SUPPORT] The characteristics defining the disease are hyperuricemia, neurodevelopmental abnormalities with global developmental delay, involuntary movements, and self-injurious behavior. --- Explanation: Lists global developmental delay as a defining characteristic.


MONDO:0010298

[PMID:18067674] [SUPPORT] Uric acid overproduction is present inall HPRT-deficient patients and is associated with lithiasis and gout. --- Explanation: Confirms universal uric acid overproduction in all HPRT-deficient patients.


MONDO:0010298

[PMID:19259384] [SUPPORT] LND is characterized by overproduction of uric acid, leading to gouty arthritis and nephrolithiasis. --- Explanation: Confirms gout as a clinical feature of LND.


MONDO:0010298

[PMID:22198833] [SUPPORT] All of these phenotypes are associated with marked overproduction of uric acid and related problems such as hyperuricemia, urate nephrolithiasis, tophi, and gout. --- Explanation: Lists urate nephrolithiasis as a complication of uric acid overproduction.


MONDO:0010298

[PMID:8156315] [SUPPORT] Acute renal failure secondary to crystal nephropathy and tophaceous gout are unusual presenting features of this rare condition. --- Explanation: Documents acute renal failure from crystal nephropathy as a presenting feature of Lesch-Nyhan syndrome.


MONDO:0010298

[PMID:18067674] [SUPPORT] Megaloblastic anaemia is also associated with the disease. --- Explanation: Confirms megaloblastic anemia as an associated feature.


MONDO:0010298

[PMID:32310539] [INDIRECT EVIDENCE] [SUPPORT] The enzyme is responsible for recycling purines by converting guanine and hypoxanthine into guanosine monophosphate and inosine monophosphate, respectively. Lack of the enzyme causes an increase in guanine and hypoxanthine, which eventually is converted into uric acid. --- Explanation: Describes the metabolic basis of purine overproduction and uric acid accumulation.

[PMID:22198833] [INDIRECT EVIDENCE] [SUPPORT] The pathogenesis of overproduction of uric acid in HPRT deficiency is well-understood, and treatments are available to control it. --- Explanation: Confirms that uric acid overproduction mechanism is well-established.

[DOI:10.1186/s10020-023-00774-8] [INDIRECT EVIDENCE] [SUPPORT] To compensate this deficiency, there is an acceleration of the de novo purine biosynthetic pathway. --- Explanation: Demonstrates accelerated de novo purine synthesis in LND fibroblasts as a compensatory mechanism for HPRT deficiency.


MONDO:0010298


MONDO:0010298

[PMID:10760551] [INDIRECT EVIDENCE] [SUPPORT] neurochemical studies have demonstrated 60-90% reductions in the dopamine content of the basal ganglia --- Explanation: Quantifies the severe dopamine loss in the basal ganglia of LND patients.

[PMID:24891139] [INDIRECT EVIDENCE] [SUPPORT] neurons of the substantia nigra from the LND cases showed reduced melanization and reduced immunoreactivity for tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis --- Explanation: Demonstrates loss of dopaminergic phenotype in midbrain neurons without neurodegeneration.

[PMID:10760551] [INDIRECT EVIDENCE] [SUPPORT] These findings support the proposal that many of the neurobehavioral features of LND might be related to dysfunction of the basal ganglia. --- Explanation: Supports the central role of basal ganglia dysfunction in LND neurobehavioral features.

[DOI:10.1007/s12035-023-03266-2] [INDIRECT EVIDENCE] [SUPPORT] One of the hallmarks of LNS is maximal expression of HPRT in the central nervous system with the highest activity of this enzyme in the midbrain and basal ganglia. --- Explanation: Demonstrates that HPRT is maximally expressed in the midbrain and basal ganglia, explaining why these regions are most affected in LNS.


MONDO:0010298

[DOI:10.1007/s12035-023-03266-2] [INDIRECT EVIDENCE] [SUPPORT] We found that HPRT1 deficiency inhibits complex I-dependent mitochondrial respiration resulting in increased levels of mitochondrial NADH, reduction of the mitochondrial membrane potential, and increased rate of reactive oxygen species (ROS) production in mitochondria and cytosol. --- Explanation: Demonstrates that HPRT1 deficiency directly impairs mitochondrial complex I respiration and increases ROS in murine neurons.

[DOI:10.1007/s12035-023-03266-2] [INDIRECT EVIDENCE] [SUPPORT] Thus, disruption of mitochondrial energy metabolism but not oxidative stress could play a role of potential trigger of brain pathology in LNS. --- Explanation: Concludes that mitochondrial energy disruption rather than oxidative stress is the key pathological mechanism.


MONDO:0010298

[DOI:10.1186/s10020-023-00774-8] [INDIRECT EVIDENCE] [SUPPORT] LND fibroblasts maintained with Plasmax-PV show metabolic adaptations such a higher glycolytic capacity, increased expression of the folate carrier SCL19A1, and functional alterations such a decreased mitochondrial potential and reduced cell migration compared to controls. --- Explanation: Demonstrates multiple cellular alterations in LND fibroblasts under physiological culture conditions, including metabolic and functional changes.

[DOI:10.1186/s10020-023-00774-8] [INDIRECT EVIDENCE] [SUPPORT] These alterations can be reverted with high levels of folic acid, suggesting that folic acid supplements might be a potential treatment for LND. --- Explanation: Shows that folic acid supplementation can reverse the cellular alterations caused by ZMP accumulation in LND fibroblasts.


MAXO:0000058

[PMID:18067674] [SUPPORT] Uric acid overproduction can be managed by allopurinol treatment. --- Explanation: Confirms allopurinol as the standard treatment for uric acid overproduction.


CHEBI:40279

[PMID:18067674] [INDIRECT EVIDENCE] [SUPPORT] Uric acid overproduction can be managed by allopurinol treatment. --- Explanation: Confirms allopurinol as the standard treatment for uric acid overproduction.


MAXO:0000950

[PMID:18067674] [SUPPORT] Self-injurious behaviour must be managed by a combination of physical restraints, behavioural and pharmaceutical treatments. --- Explanation: Describes the multimodal approach to managing self-injurious behavior.


MAXO:0000011

[PMID:18067674] [SUPPORT] Physical rehabilitation, including management of dysarthria and dysphagia, special devices to enable hand control, appropriate walking aids, and a programme of posture management to prevent deformities are recommended. --- Explanation: Describes the comprehensive rehabilitation approach.


MAXO:0000943

[PMID:36694014] [SUPPORT] DBS improved dystonia of the LNS to varying degrees. All the included cases achieved partial or complete control of self-injurious behavior (SIB). Overall, DBS is a promising treatment for both motor and behavior disorders of LNS patients, but the results reported thus far have varied widely, especially for motor outcomes. --- Explanation: Systematic review of 12 LNS patients showing DBS improved dystonia and achieved partial or complete control of self-injurious behavior.


hgnc:5157

[PMID:18067674] [SUPPORT] Human HPRT is encoded by a single structural gene on the long arm of the X chromosome at Xq26. To date, more than 300 disease-associated mutations in the HPRT1 gene have been identified. --- Explanation: Documents HPRT1 as the causative gene with over 300 known mutations.

[PMID:32310539] [SUPPORT] Lesch Nyhan syndrome is an inborn disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme, an enzyme of the purine salvage pathway. --- Explanation: Confirms HPRT enzyme deficiency as the cause of Lesch-Nyhan syndrome.


MONDO:0010298

[PMID:18067674] [SUPPORT] Inheritance of HPRT deficiency is X-linked recessive, thus males are generally affected and heterozygous female are carriers (usually asymptomatic). --- Explanation: Confirms X-linked recessive inheritance with males affected and carrier females typically asymptomatic.


MONDO:0018875

[PMID:26014290] [SUPPORT] In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. --- Explanation: French cohort study of 415 TP53 mutation carriers demonstrates soft tissue sarcomas are a core tumor type in LFS, occurring in 23% of children and 27% of adults.


MONDO:0018875


MONDO:0018875

[PMID:26014290] [SUPPORT] In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. --- Explanation: French cohort study demonstrates breast cancer is the predominant tumor type in adult females with LFS, occurring in 79% of affected women.


MONDO:0018875

[PMID:26014290] [SUPPORT] The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. --- Explanation: Large French cohort demonstrates that 43% of LFS patients develop multiple malignancies, with average 1.7 tumors per affected carrier.


MAXO:0000126

[PMID:28572266] [SUPPORT] the panel recommends adoption of a modified version of the "Toronto protocol" that includes a combination of physical exams, blood tests, and imaging. The panel also recommends that further research be promoted to explore the feasibility and effectiveness of these risk-adapted surveillance and cancer prevention strategies. --- Explanation: AACR expert panel consensus recommends the Toronto Protocol surveillance approach for all LFS patients as soon as diagnosis is established.


MAXO:0000004


MAXO:0000079


HGNC.SYMBOL:TP53

[PMID:26014290] [SUPPORT] The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations. --- Explanation: Clinical gradient of germline TP53 mutations demonstrates that dominant-negative missense mutations cause earlier tumor onset (21.3 years) compared to loss-of-function mutations (28.5 years), supporting mutation-specific phenotype stratification.


MONDO:0006585

[PMID:40855389] [SUPPORT] Lichen simplex chronicus (LSC), also known as neurodermatitis, is a common chronic pruritic dermatosis defined by lichenified plaques resulting from persistent scratching. --- Explanation: The abstract defines LSC as a pruritic dermatosis with lichenified plaques from scratching.


MONDO:0013762

[PMID:22152680] [SUPPORT] an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine
 --- Explanation: The index LIAS-deficient patient presented with neonatal-onset epilepsy as a prominent clinical feature.

[PMID:24334290] [SUPPORT] Patients with lipoate synthase-deficient variant nonketotic hyperglycinemia varied in severity from mild static encephalopathy to Leigh disease and cortical involvement.
 --- Explanation: Baker et al. confirm seizures and encephalopathy as features of LIAS deficiency across a wider spectrum of severity.


MONDO:0013762

[PMID:22152680] [SUPPORT] an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine
 --- Explanation: The index patient presented with muscular hypotonia as one of the cardinal features of LIAS deficiency.


MONDO:0013762

[PMID:22152680] [SUPPORT] an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine
 --- Explanation: Lactic acidosis was a cardinal biochemical finding in the index LIAS-deficient patient.

[PMID:24334290] [PARTIAL] They had low pyruvate dehydrogenase enzyme activity but most did not have lactic acidosis.
 --- Explanation: In the Baker et al. cohort, most LIAS patients had low PDH activity but lactic acidosis was not consistently present, suggesting variable severity.


MONDO:0013762

[PMID:22152680] [SUPPORT] elevated glycine concentration in plasma and urine
 --- Explanation: The index patient had elevated glycine in both plasma and urine, consistent with impaired glycine cleavage system function.

[PMID:24334290] [SUPPORT] All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio, and deficient glycine cleavage enzyme activity.
 --- Explanation: In the Baker et al. cohort, all variant NKH patients including those with LIAS mutations had elevated glycine and deficient glycine cleavage.


MONDO:0013762

[PMID:24334290] [SUPPORT] Patients with lipoate synthase-deficient variant nonketotic hyperglycinemia varied in severity from mild static encephalopathy to Leigh disease and cortical involvement.
 --- Explanation: Baker et al. describe a range of severity in LIAS patients from mild encephalopathy to Leigh disease, confirming neurodevelopmental impairment as a consistent feature.


MONDO:0013762

[PMID:32508887] [SUPPORT] severe respiratory deficiency and extreme muscle weakness due to citric acid cycle disfunction plus the neurological impairments caused by glycine accumulation in the brain --- Explanation: The combined respiratory deficiency, muscle weakness, and neurological impairment described in LIAS patients contributes to failure to thrive.


MONDO:0013762

[PMID:24334290] [SUPPORT] Patients with lipoate synthase-deficient variant nonketotic hyperglycinemia varied in severity from mild static encephalopathy to Leigh disease and cortical involvement. --- Explanation: Baker et al. describe cortical involvement and progression to Leigh disease in LIAS patients, consistent with cerebral atrophy.


MONDO:0013762


MONDO:0013762

[PMID:22152680] [INDIRECT EVIDENCE] [SUPPORT] Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate and decreased pyruvate dehydrogenase complex activity. A pronounced reduction of the prosthetic group lipoamide was found in lipoylated proteins.
 --- Explanation: Patient fibroblasts showed reduced PDH activity and decreased lipoylation, confirming that LIAS loss of function impairs the lipoylation pathway.

[PMID:32508887] [INDIRECT EVIDENCE] [SUPPORT] LIAS was the sulfur insertion enzyme
 --- Explanation: Review establishes that LIAS is the enzyme responsible for inserting sulfur atoms into octanoyl-GCSH during lipoic acid assembly.


MONDO:0013762

[PMID:32508887] [INDIRECT EVIDENCE] [SUPPORT] Patients that display absent or low lipoylation of all three enzymes have mutations in either of two genes LIAS or LIPT2
 --- Explanation: Review confirms that LIAS and LIPT2 mutations both result in absent or low lipoylation of all lipoic acid-dependent enzyme complexes, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and the glycine cleavage system.

[PMID:32508887] [INDIRECT EVIDENCE] [SUPPORT] patients defective in either of these genes have undetectable or severely decreased levels of all lipoylated proteins and undergo the severe respiratory deficiency and extreme muscle weakness due to citric acid cycle disfunction plus the neurological impairments caused by glycine accumulation in the brain
 --- Explanation: Review explains the biochemical and clinical consequences of combined dehydrogenase and glycine cleavage deficiency in LIAS patients.


MAXO:0000950

[PMID:24334290] [SUPPORT] Treatments of cells with lipoate and with mitochondrially-targeted lipoate were unsuccessful at correcting the deficiency.
 --- Explanation: Baker et al. demonstrated that lipoic acid supplementation, even with mitochondrially-targeted forms, failed to correct the biochemical deficiency in patient cells, supporting the need for purely supportive care.

[PMID:32508887] [SUPPORT] lipoic acid supplementation of the diets of human LIAS, LIPT1, and LIPT2 patients or of their fibroblast cultures failed to alleviate the physiological and biochemical effects of the mutant genes
 --- Explanation: Review confirms that lipoic acid supplementation is ineffective in LIAS patients, as exogenous lipoate cannot enter the mitochondrial de novo synthesis pathway.


MAXO:0000058

[PMID:39547509] [SUPPORT] This synthetic approach offers a potential therapeutic strategy for treating lipoylation disorders. --- Explanation: Bick et al. demonstrated that engineered bacterial lplA could restore lipoylation in LIAS knockout cell models, providing proof of concept for a therapeutic bypass of the defective de novo synthesis pathway.


HGNC.SYMBOL:LIAS loss-of-function variants

[PMID:22152680] [SUPPORT] We identified the homozygous mutation c.746G>A (p.Arg249His) in LIAS in an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine.
 --- Explanation: First report of a causal LIAS mutation: homozygous c.746G>A (p.Arg249His) in the index patient.

[PMID:24334290] [SUPPORT] Mutations were identified in the genes for lipoate synthase (LIAS), BolA type 3 (BOLA3), and a novel gene glutaredoxin 5 (GLRX5).
 --- Explanation: Baker et al. identified additional LIAS mutations in a larger cohort of variant NKH patients, confirming LIAS as a causal gene.

[PMID:24334290] [SUPPORT] transfection with native genes corrected the biochemical deficiency proving pathogenicity.
 --- Explanation: Functional validation by gene complementation confirmed that the identified LIAS mutations were pathogenic.