MONDO:0010857

[PMID:41089414] [SUPPORT] Associated features include surface dyslexia, prosopagnosia, relatively preserved speech production, and emotional or behavioral abnormalities. --- Explanation: The abstract notes behavioral abnormalities as associated features.


MAXO:0000950

[PMID:28286641] [PARTIAL] The purpose of this paper is to gain consensus regarding the clinical priorities and tasks required in supporting communication needs in those living with semantic dementia and their families, by specialist speech and language therapists (SLTs), working in clinical practice within dementia care settings in the UK. --- Explanation: The abstract describes speech and language therapist-led communication support for semantic dementia.


MONDO:0018484

[PMID:16222184] [SUPPORT] For the 60 patients with vestibular manifestations, symptoms induced by loud sounds were noted in 54 patients and pressure-induced symptoms (coughing, sneezing, straining) were present in 44. --- Explanation: The original clinical series demonstrates that the vast majority of SCDS patients experience sound- or pressure-induced vestibular symptoms.


MONDO:0018484

[PMID:32982922] [SUPPORT] Sound-evoked vertigo or nystagmus are now termed "Tullio phenomenon," often exhibited as a symptom of third window syndrome. --- Explanation: The biomechanics review confirms that sound-evoked nystagmus (Tullio phenomenon) is a characteristic feature of third window syndrome.


MONDO:0018484

[PMID:32982922] [SUPPORT] Symptoms include vestibular indications such as eye movements or dizziness evoked by sound or middle ear/intracranial pressure changes, chronic disequilibrium, oscillopsia --- Explanation: Oscillopsia is listed as one of the vestibular symptoms in SCDS.


MONDO:0018484

[PMID:32982922] [SUPPORT] and auditory indications such as autophony, hyperacusis for bone-conducted sounds, conductive hearing loss, and tinnitus. --- Explanation: Autophony is described as a characteristic auditory symptom of SCDS.


MONDO:0018484

[PMID:22312921] [SUPPORT] The patient developed bilateral aural fullness, pulsatile tinnitus, and difficulty tolerating loud noises after minor head trauma at 53 years of age. --- Explanation: Pulsatile tinnitus is documented as a presenting symptom in this SCDS case.


MONDO:0018484

[PMID:18223508] [SUPPORT] The CHL results by the dual mechanism of worsening of air conduction thresholds and improvement of bone conduction thresholds. --- Explanation: This landmark paper explains the mechanism of pseudoconductive hearing loss in third window lesions.

[PMID:16222184] [SUPPORT] An air-bone on audiometry in these patients with vestibular manifestations measured (mean +/- SD) 19 +/- 14 dB at 250 Hz; 15 +/- 11 dB at 500 Hz; 11 +/- 9 dB at 1,000 Hz; and 4 +/- 6 dB at 2,000 Hz. --- Explanation: Clinical data demonstrates the characteristic low-frequency air-bone gap pattern in SCDS patients.


MONDO:0018484

[PMID:32982922] [SUPPORT] Symptoms include vestibular indications such as eye movements or dizziness evoked by sound or middle ear/intracranial pressure changes, chronic disequilibrium, oscillopsia --- Explanation: Chronic disequilibrium is listed as one of the vestibular symptoms in SCDS.


MONDO:0018484

[PMID:32982922] [SUPPORT] and auditory indications such as autophony, hyperacusis for bone-conducted sounds, conductive hearing loss, and tinnitus. --- Explanation: Hyperacusis is listed as an auditory symptom of SCDS.


MONDO:0018484

[PMID:22312921] [INDIRECT EVIDENCE] [SUPPORT] Histopathologic examination of the right ear showed a 1.4 x 0.6-mm dehiscence of bone covering the superior canal. Dura was in direct contact with the endosteum and the membranous duct at the level of the dehiscence. --- Explanation: Histopathological examination confirmed the anatomical basis of the dehiscence with direct dura-to-membranous duct contact at the bony defect.


MONDO:0018484


MONDO:0018484

[PMID:32982922] [INDIRECT EVIDENCE] [SUPPORT] If sufficiently large, a third window will introduce a low mechanical impedance, thus shunting part of the inner ear fluid pressure and fluid volume flow at the site of the window. --- Explanation: This biomechanical review explains how the dehiscence creates abnormal fluid dynamics by introducing a low-impedance pathway.

[PMID:18223508] [INDIRECT EVIDENCE] [SUPPORT] A number of disparate disorders affecting the labyrinth can produce CHL by acting as a pathologic third window in the inner ear. The common denominator is that these conditions result in a mobile window on the scala vestibuli side of the cochlear partition. --- Explanation: This landmark paper establishes the third window mechanism as the cause of the conductive hearing loss pattern seen in SCDS.


MONDO:0018484

[PMID:32982922] [INDIRECT EVIDENCE] [SUPPORT] Third window syndrome describes a set of vestibular and auditory symptoms that arise when a pathological third mobile window is present in the bony labyrinth of the inner ear. --- Explanation: The biomechanics review explains how the third window allows sound and pressure to inappropriately stimulate vestibular structures.

[PMID:16222184] [INDIRECT EVIDENCE] [SUPPORT] For the 60 patients with vestibular manifestations, symptoms induced by loud sounds were noted in 54 patients and pressure-induced symptoms (coughing, sneezing, straining) were present in 44. --- Explanation: Clinical data from the original case series demonstrates the high frequency of sound- and pressure-induced symptoms in SCDS patients.


MONDO:0018484

[PMID:22312921] [INDIRECT EVIDENCE] [SUPPORT] No osteoclastic process was evident within the otic capsule bone surrounding the dehiscence. --- Explanation: Histopathological examination showed absence of active bone resorption, supporting developmental thin-bone predisposition rather than active resorption.


MAXO:0000004

[PMID:16222184] [SUPPORT] Canal plugging was performed in 9 and resurfacing of the canal without plugging of the lumen in 11 patients. Complete resolution of vestibular symptoms and signs was achieved in 8 of the 9 patients after canal plugging. --- Explanation: Clinical data demonstrates high success rate of canal plugging surgery.

[PMID:32982922] [SUPPORT] Canal plugging achieves long-term control more often than resurfacing and is usually the procedure of choice --- Explanation: Canal plugging is established as the preferred surgical treatment.


MAXO:0000004

[PMID:16222184] [SUPPORT] Complete resolution of vestibular symptoms and signs was achieved in 8 of the 9 patients after canal plugging and in 7 of the 11 patients after resurfacing. --- Explanation: Resurfacing can achieve symptom resolution, though less reliably than plugging.

[PMID:36742050] [SUPPORT] The changes observed also reverse and return to baseline as the SSCD heals by bone resurfacing (with the lumen intact). --- Explanation: Animal model demonstrates that bony resurfacing can restore normal function while preserving canal lumen patency.


MONDO:0008922

[DOI:10.3389/fped.2021.639687] [SUPPORT] Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation. --- Explanation: This case report documents hypertrophic cardiomyopathy as a core feature of Sengers syndrome.

[DOI:10.1186/s13052-022-01370-y] [SUPPORT] Sengers syndrome is characterized by congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with mutations in AGK gene. --- Explanation: This longitudinal case report reiterates hypertrophic cardiomyopathy as a defining feature.


MONDO:0008922

[DOI:10.3389/fped.2021.639687] [SUPPORT] Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation. --- Explanation: This identifies bilateral cataracts as a defining phenotype in Sengers syndrome.

[DOI:10.1186/s13052-022-01370-y] [SUPPORT] Sengers syndrome is characterized by congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with mutations in AGK gene. --- Explanation: This report highlights congenital cataract as a core feature.


MONDO:0008922

[DOI:10.3389/fped.2021.639687] [SUPPORT] Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation. --- Explanation: This case report includes myopathy among core Sengers syndrome features.

[DOI:10.1186/s13052-022-01370-y] [SUPPORT] Sengers syndrome is characterized by congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with mutations in AGK gene. --- Explanation: This report specifies mitochondrial myopathy as a defining feature.


MONDO:0008922

[DOI:10.3389/fped.2021.639687] [SUPPORT] Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation. --- Explanation: This report documents lactic acidosis as a characteristic feature of Sengers syndrome.

[DOI:10.1186/s13052-022-01370-y] [SUPPORT] Sengers syndrome is characterized by congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with mutations in AGK gene. --- Explanation: This longitudinal case report includes lactic acidosis as a defining feature.


MONDO:0008922

[DOI:10.3389/fped.2021.639687] [SUPPORT] Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation. --- Explanation: Heart failure is reported as the most severe clinical manifestation in these cases.

[PMID:34164355] [SUPPORT] NT-proBNP reached 6,076 pg/ml (reference ranges <125 pg/ml) reflecting the state of the heart failure. --- Explanation: This case report documents biochemical evidence of heart failure in a Sengers syndrome patient.


MONDO:0008922

[DOI:10.1186/s13052-022-01370-y] [SUPPORT] Here we provide a 20-year follow-up in two siblings with a benign form of Sengers syndrome, expanding the phenotypical spectrum of the disease by reporting a condition of ovarian agenesis. --- Explanation: This report documents ovarian agenesis, consistent with ovarian aplasia.


MONDO:0008922

[DOI:10.3390/ijms222413484] [INDIRECT EVIDENCE] [SUPPORT] AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the inner mitochondrial membrane, which mediates the import of a subset of membrane proteins. --- Explanation: This establishes AGK's role in lipid signaling that is lost with AGK deficiency.


MONDO:0008922

[DOI:10.3390/ijms222413484] [INDIRECT EVIDENCE] [SUPPORT] AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the inner mitochondrial membrane, which mediates the import of a subset of membrane proteins. --- Explanation: This supports a TIM22 assembly defect at the mitochondrial inner membrane in AGK deficiency.


MONDO:0008922

[DOI:10.1091/mbc.e20-06-0390] [INDIRECT EVIDENCE] [SUPPORT] Proteomic profiling of Sengers patient fibroblasts and AGK knockout models identifies remodeling of the mitochondrial proteome, including mitochondrial one-carbon metabolism enzymes, inner membrane serine transporters, sideroflexins, and Complex I subunits and assembly factors. --- Explanation: This supports reduced import/abundance of inner-membrane carriers and sideroflexins in AGK deficiency.


MONDO:0008922

[DOI:10.1091/mbc.e20-06-0390] [INDIRECT EVIDENCE] [SUPPORT] Proteomic profiling of Sengers patient fibroblasts and AGK knockout models identifies remodeling of the mitochondrial proteome, including mitochondrial one-carbon metabolism enzymes, inner membrane serine transporters, sideroflexins, and Complex I subunits and assembly factors. --- Explanation: This links AGK/TIM22 dysfunction to loss of carrier and sideroflexin import with effects on one-carbon metabolism.


MONDO:0008922

[DOI:10.3390/ijms222413484] [INDIRECT EVIDENCE] [SUPPORT] AGK mutations can alter both phospholipid metabolism and mitochondrial protein biogenesis, contributing to the pathogenesis of Sengers syndrome. --- Explanation: This statement links AGK mutations to altered phospholipid metabolism in Sengers syndrome.


MONDO:0008922

[DOI:10.3390/ijms222413484] [INDIRECT EVIDENCE] [SUPPORT] Decreases in the oxygen consumption rate (OCR) and the OCR:ECAR (extracellular acidification rate) ratio in the patient’s fibroblasts indicated reduced electron flow through the respiratory chain, and spectrophotometry revealed decreased activity of OXPHOS complexes I and V. --- Explanation: This provides direct evidence of impaired oxidative phosphorylation and reduced complex I and V activity.


MAXO:0010012

[PMID:34164355] [SUPPORT] Supplementation with coenzyme Q10, carnitine, B-vitamins, and biotin (called mitochondrial cocktail) was given daily, associated with angiotensin converting enzyme (ACE) inhibitors for cardiomyopathy management. --- Explanation: This case report lists coenzyme Q10 as part of a mitochondrial cocktail for Sengers syndrome.

[PMID:34164355] [SUPPORT] Levocarnitine (100 mg/kg daily), coenzyme Q10 (1 mg/kg daily), and vitamin B complex (vitamin B1 20 mg/day and riboflavin 10 mg/day) were administered to improve metabolic status; --- Explanation: This provides dosing detail confirming coenzyme Q10 use in Sengers syndrome.


MAXO:0010006

[PMID:34164355] [SUPPORT] Supplementation with coenzyme Q10, carnitine, B-vitamins, and biotin (called mitochondrial cocktail) was given daily, associated with angiotensin converting enzyme (ACE) inhibitors for cardiomyopathy management. --- Explanation: This case report lists carnitine within the mitochondrial cocktail for Sengers syndrome.

[PMID:34164355] [SUPPORT] Levocarnitine (100 mg/kg daily), coenzyme Q10 (1 mg/kg daily), and vitamin B complex (vitamin B1 20 mg/day and riboflavin 10 mg/day) were administered to improve metabolic status; --- Explanation: This provides dosing detail confirming levocarnitine use in Sengers syndrome.


MAXO:0000761

[PMID:34164355] [SUPPORT] Supplementation with coenzyme Q10, carnitine, B-vitamins, and biotin (called mitochondrial cocktail) was given daily, associated with angiotensin converting enzyme (ACE) inhibitors for cardiomyopathy management. --- Explanation: This case report lists B-vitamins within the mitochondrial cocktail for Sengers syndrome.

[PMID:34164355] [SUPPORT] Levocarnitine (100 mg/kg daily), coenzyme Q10 (1 mg/kg daily), and vitamin B complex (vitamin B1 20 mg/day and riboflavin 10 mg/day) were administered to improve metabolic status; --- Explanation: This provides dosing detail confirming vitamin B complex use in Sengers syndrome.


MAXO:0000652

[PMID:34164355] [SUPPORT] Supplementation with coenzyme Q10, carnitine, B-vitamins, and biotin (called mitochondrial cocktail) was given daily, associated with angiotensin converting enzyme (ACE) inhibitors for cardiomyopathy management. --- Explanation: This case report notes ACE inhibitor use alongside mitochondrial cocktail therapy.

[PMID:34164355] [SUPPORT] The patient received milrinone, diuretics (furosemide and spironolactone), and captopril to improve heart function. --- Explanation: This provides direct evidence of ACE inhibitor (captopril) therapy in Sengers syndrome.

[PMID:38933059] [SUPPORT] Baby was on regular follow-up and was thriving well on diuretics, sacubitril-valsartan and weekly levosimendan infusions. --- Explanation: This neonatal case reports ongoing pharmacologic heart failure management including a neprilysin inhibitor/ARB regimen.


MAXO:0010032

[PMID:8526648] [SUPPORT] This report describes cardiac transplantation for the treatment of the cardiomyopathy associated with Sengers' syndrome. --- Explanation: This case report documents cardiac transplantation as a treatment for Sengers-associated cardiomyopathy.

[PMID:38933059] [SUPPORT] At 8 months of age, cardiac transplantation was successfully done and baby has been doing well post-transplantation. --- Explanation: This neonatal case report describes successful cardiac transplantation in Sengers syndrome.


MAXO:0000165

[PMID:38933059] [SUPPORT] Baby was on regular follow-up and was thriving well on diuretics, sacubitril-valsartan and weekly levosimendan infusions. --- Explanation: This case report documents ongoing diuretic therapy as part of heart failure management.

[PMID:34164355] [SUPPORT] The patient received milrinone, diuretics (furosemide and spironolactone), and captopril to improve heart function. --- Explanation: This provides direct evidence of diuretic use in Sengers syndrome.


MAXO:0000058

[PMID:38933059] [SUPPORT] Baby was on regular follow-up and was thriving well on diuretics, sacubitril-valsartan and weekly levosimendan infusions. --- Explanation: This neonatal case report describes levosimendan infusions in Sengers syndrome.


HGNC.SYMBOL:AGK

[DOI:10.3389/fped.2021.639687] [SUPPORT] Sengers syndrome (OMIM #212350) is a rare autosomal recessive disorder due to mutations in acylglycerol kinase (AGK) gene. --- Explanation: This statement identifies AGK mutations as the cause of Sengers syndrome with autosomal recessive inheritance.

[PMID:34164355] [SUPPORT] After genetic analysis, a novel homozygous (c.1131+2T>C) variant of AGK gene was identified in the proband. --- Explanation: This case report provides direct genetic evidence of a pathogenic AGK variant in Sengers syndrome.


MONDO:0008922

[DOI:10.3389/fped.2021.639687] [SUPPORT] Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation. --- Explanation: This report documents lactic acidosis as a core biochemical abnormality.

[PMID:34164355] [SUPPORT] However, the serum lactic acid increased significantly, reaching 14.99 mmol/L, so appropriate limitation of physical activities is recommended in daily life. --- Explanation: This case report provides quantitative evidence of markedly elevated serum lactic acid.


MONDO:0008922

[PMID:34164355] [SUPPORT] Urinary organic acid analysis showed increased amounts of 3-hydroxybutyrate (25.5 mmol/L, normal <9.0 mmol/L) --- Explanation: This report documents elevated 3-hydroxybutyrate on urinary organic acid analysis.


MONDO:0019345

[PMID:29493962] [SUPPORT] The main symptom of shigellosis is bloody and often mucoid diarrhea; abdominal pain and vomiting are common --- Explanation: Establishes diarrhea as a cardinal clinical feature of shigellosis resulting from epithelial damage and inflammatory secretion


MONDO:0019345

[PMID:37952487] [PARTIAL] bacillary dysentery, a severe enteric disease characterized by destruction and inflammation of the colonic epithelium accompanied by acute diarrhea, fever, and abdominal pain --- Explanation: Establishes bloody diarrhea as the defining characteristic of Shigella pathogenesis due to colonic epithelial destruction


MONDO:0019345

[PMID:29493962] [SUPPORT] abdominal pain and vomiting are common --- Explanation: Confirms abdominal pain as a cardinal clinical manifestation of shigellosis


MONDO:0019345

[PMID:40915309] [NO_EVIDENCE] Globally, shigellosis is the most common cause of invasive bloody diarrhoea in children younger than 5 years --- Explanation: Fever is a component of the invasive inflammatory response characteristic of shigellosis in children


MONDO:0019345

[PMID:29493962] [PARTIAL] Supportive care may be required, and antibiotics could shorten the duration of illness or prevent complications --- Explanation: Fluid and electrolyte replacement represents supportive care for dehydration-related complications of shigellosis


MONDO:0019345

[PMID:40915309] [INDIRECT EVIDENCE] [NO_EVIDENCE] Humans are the only natural reservoir and an inoculum of only 10-100 organisms is required for infection --- Explanation: Highlights the extraordinary efficiency of Shigella invasion, demonstrating that the T3SS-mediated invasion mechanism is highly optimized for intracellular entry


MONDO:0019345


MONDO:0019345

[PMID:37952487] [INDIRECT EVIDENCE] [PARTIAL] destruction and inflammation of the colonic epithelium accompanied by acute diarrhea, fever, and abdominal pain --- Explanation: Describes the characteristic tissue damage phenotype resulting from Shigella's actin-based cell-to-cell spread and mucosal invasion


MONDO:0019345

[PMID:29493962] [INDIRECT EVIDENCE] [PARTIAL] In the colon, they secrete virulence factors that cause severe inflammation and mediate enterotoxic effects, enabling colonization and invasion of the colonic epithelium --- Explanation: Establishes inflammasome-mediated pyroptosis and cytokine release as central to Shigella pathogenesis


MONDO:0019345

[PMID:29493962] [INDIRECT EVIDENCE] [PARTIAL] Shigella produces 3 enterotoxins that cause watery or bloody diarrhea and infection-associated symptoms --- Explanation: Enterotoxins and Shiga toxins are key virulence factors causing epithelial damage and systemic complications


MONDO:0019345

[PMID:37952487] [INDIRECT EVIDENCE] [PARTIAL] a severe enteric disease characterized by destruction and inflammation of the colonic epithelium --- Explanation: Epithelial destruction is the hallmark of Shigella pathogenesis, directly causing barrier dysfunction


MAXO:0000058

[PMID:29493962] [PARTIAL] antibiotics could shorten the duration of illness or prevent complications, particularly in individuals at increased risk for severe disease --- Explanation: Antimicrobial therapy is indicated to reduce bacterial load and prevent systemic complications

[PMID:36409683] [PARTIAL] WHO-recommended 1st line antibiotic ciprofloxacin resistance gradually reached more than 70% in both the urban and rural site by 2020 --- Explanation: Rising antimicrobial resistance, especially to fluoroquinolones, necessitates susceptibility-guided therapy


MAXO:0000950

[PMID:29493962] [PARTIAL] Supportive care may be required, and antibiotics could shorten the duration of illness or prevent complications --- Explanation: Oral rehydration is the first-line approach to managing fluid and electrolyte losses


MAXO:0000950

[PMID:40915309] [NO_EVIDENCE] an inoculum of only 10-100 organisms is required for infection --- Explanation: Severe fluid losses from Shigella-mediated diarrhea may necessitate intravenous fluid replacement


HGNC.SYMBOL:NLRC4 (NOD-like receptor family CARD domain-containing 4)

[PMID:40915309] [NO_EVIDENCE] prevention of infection with vaccination and sanitation strategies remains a crucial step in reducing worldwide morbidity and mortality --- Explanation: Understanding NLRC4 genetic variation in susceptible populations informs vaccine design targeting T3SS components


HGNC.SYMBOL:NLRP3 (NLR family pyrin domain containing 3)

[PMID:40915309] [NO_EVIDENCE] Rising antibiotic resistance rates increasingly reduce the ability to adequately treat severe disease --- Explanation: NLRP3 genetic variation may contribute to inter-individual differences in disease severity and treatment response


HGNC.SYMBOL:CASP1 (Caspase-1)

[PMID:29493962] [NO_EVIDENCE] Shigella produces 3 enterotoxins that cause watery or bloody diarrhea and infection-associated symptoms, eg, tenesmus, malaise, and fever --- Explanation: CASP1-mediated pyroptosis in response to Shigella T3SS components drives the inflammatory manifestations of disease


HGNC.SYMBOL:GSDMD (Gasdermin D)

[PMID:37952487] [NO_EVIDENCE] destruction and inflammation of the colonic epithelium accompanied by acute diarrhea, fever, and abdominal pain --- Explanation: GSDMD-mediated pore formation drives epithelial damage and loss of barrier integrity


HGNC.SYMBOL:CASP4 and CASP5 (Non-canonical inflammasome caspases)

[PMID:29493962] [NO_EVIDENCE] Shigella produces 3 enterotoxins that cause watery or bloody diarrhea and infection-associated symptoms --- Explanation: CASP4/5-mediated non-canonical inflammasome activation in response to bacterial LPS contributes to mucosal damage


HGNC.SYMBOL:TLR1 and TLR2 (Toll-like receptors)

[PMID:37952487] [NO_EVIDENCE] The human-specific nature of shigellosis and the absence of a dependable animal model have posed significant obstacles in understanding Shigella pathogenesis --- Explanation: TLR1/TLR2 polymorphisms likely contribute to the observed variation in disease severity across populations with different genetic backgrounds


HGNC.SYMBOL:Lewis blood group antigens (ABO/Lewis glycosylation)

[PMID:32940644] [SUPPORT] lack of the Lewis histo-blood group antigen was associated with increased susceptibility to shigellosis --- Explanation: Genetic control of glycan biosynthesis influences epithelial cell susceptibility to Shigella invasion


NCBITaxon:620

[PMID:40915309] [PARTIAL] Shigella is a Gram-negative, facultative intracellular, gastric acid-resistant bacterium of the Enterobacteriaceae family, which includes four serogroups --- Explanation: Establishes Shigella as the causative agent of shigellosis and describes its key microbiologic features


MONDO:0015461

[PMID:24183449] [SUPPORT] characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period --- Explanation: Describes the cardinal skeletal features of SRP type III including short ribs and perinatal lethality.

[PMID:19442771] [PARTIAL] Jeune asphyxiating thoracic dystrophy (ATD) is an autosomal-recessive chondrodysplasia characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and trident acetabular roof --- Explanation: Confirms short ribs as characteristic of the ATD-SRP spectrum.


MONDO:0015461

[PMID:24183449] [SUPPORT] characterized by short ribs, a narrow thorax, short long bones --- Explanation: Narrow thorax is a defining feature of SRP type III.


MONDO:0015461

[PMID:19442771] [PARTIAL] short ribs and a narrow thorax, short long bones, inconstant polydactyly --- Explanation: Polydactyly is a variable but recognized feature in the ATD-SRP spectrum.


MONDO:0015461

[PMID:24183449] [SUPPORT] characterized by short ribs, a narrow thorax, short long bones --- Explanation: Short long bones are part of the defining phenotype.


MONDO:0015461

[PMID:24183449] [NO_EVIDENCE] numerous extraskeletal malformations --- Explanation: Renal cystic disease is among the extraskeletal malformations in SRP.


MONDO:0015461


MONDO:0015461

[PMID:22791528] [INDIRECT EVIDENCE] [SUPPORT] 10 different genes have been identified as responsible for seven "skeletal" ciliopathies. Mutations have been identified in dynein motor (DYNC2H1), in intraflagellar transport (IFT) complexes (IFT80, IFT122, IFT43, WDR35, WDR19, and TTC21B) as well as in genes responsible for the basal body (NEK1, EVC, and EVC2) --- Explanation: Comprehensive overview showing mutations across dynein, IFT, and basal body genes.

[PMID:21211617] [INDIRECT EVIDENCE] [SUPPORT] absence of functional full-length NEK1 severely reduces cilia number and alters ciliar morphology in vivo --- Explanation: Demonstrates that NEK1 loss-of-function directly impairs ciliogenesis.

[PMID:24183449] [INDIRECT EVIDENCE] [SUPPORT] primary cilia in WDR34 mutant fibroblasts were significantly shorter than normal and had a bulbous tip --- Explanation: Shows direct ciliary structural abnormalities in WDR34-mutant cells.

[PMID:19442771] [INDIRECT EVIDENCE] [SUPPORT] DYNC2H1 is a component of a cytoplasmic dynein complex and is directly involved in the generation and maintenance of cilia --- Explanation: Confirms DYNC2H1 role in ciliary generation and maintenance.


MONDO:0015461

[PMID:22791528] [INDIRECT EVIDENCE] [PARTIAL] primary cilia play a vital role in transduction of signals in the hedgehog pathway that is especially important in skeletal development --- Explanation: Establishes the role of primary cilia and hedgehog signaling in skeletal ciliopathies.


HGNC.SYMBOL:DYNC2H1 Mutations (SRP Type III/Verma-Naumoff)

[PMID:19442771] [PARTIAL] we conclude that ATD and SRP type III are variants of a single disorder belonging to the ciliopathy group --- Explanation: Landmark paper establishing that DYNC2H1 mutations cause both ATD and SRP type III, proving they are a single spectrum.

[PMID:19442771] [SUPPORT] identified homozygous mutations in the cytoplasmic dynein 2 heavy chain 1 (DYNC2H1) gene in the affected children. Compound heterozygosity for DYNC2H1 mutations was also identified in four additional families --- Explanation: Identifies DYNC2H1 mutations in both homozygous and compound heterozygous states.


HGNC.SYMBOL:NEK1 Mutations (SRP Type II/Majewski)

[PMID:21211617] [SUPPORT] We used homozygosity mapping in two families with autosomal-recessive short-rib polydactyly syndrome Majewski type to identify mutations in NEK1 as an underlying cause of this lethal osteochondrodysplasia --- Explanation: Discovery paper identifying NEK1 as the cause of SRP Majewski type.

[PMID:21211617] [SUPPORT] NEK1 encodes a serine/threonine kinase with proposed function in DNA double-strand repair, neuronal development, and coordination of cell-cycle-associated ciliogenesis --- Explanation: Characterizes NEK1 function including its role in ciliogenesis.

[PMID:21211617] [PARTIAL] We further substantiate a proposed digenic diallelic inheritance of ciliopathies by the identification of heterozygous mutations in NEK1 and DYNC2H1 in an additional family --- Explanation: Reports digenic inheritance involving NEK1 and DYNC2H1, suggesting oligogenic complexity.


HGNC.SYMBOL:WDR34 Mutations (SRP Type III)

[PMID:24183449] [SUPPORT] homozygosity for three missense mutations in WDR34 were found in three independent families, as well as compound heterozygosity for mutations in one family --- Explanation: Identifies WDR34 mutations in multiple SRP type III families.

[PMID:24183449] [SUPPORT] This report expands on the pathogenesis of SRP type III and demonstrates that a regulator of the NF-κB activation pathway is involved in the pathogenesis of the skeletal ciliopathies --- Explanation: Reveals unexpected link between NF-kappaB signaling and ciliary function in SRP.


HGNC.SYMBOL:IFT80 Mutations

[PMID:19648123] [SUPPORT] mutations in IFT80 can also be responsible for a lethal form of SRP and provide the molecular basis for the Jeune-Verma-Naumoff dysplasia spectrum --- Explanation: Demonstrates that IFT80 mutations can cause both lethal SRP and milder JATD, establishing the Jeune-Verma-Naumoff spectrum.

[PMID:19648123] [SUPPORT] Direct sequencing of IFT80 in the other 13 cases showed a G-to-C transversion in exon 8 (G241R) in only one SRP case closely related to the type III phenotype --- Explanation: Identifies specific IFT80 mutation in an SRP type III case.


MONDO:0008426

[PMID:23103230] [SUPPORT] Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. --- Explanation: Lists craniosynostosis as a characteristic feature of SGS.

[PMID:9508238] [SUPPORT] Shprintzen-Goldberg syndrome is one of a group of disorders characterized by craniosynostosis and marfanoid habitus. --- Explanation: Identifies craniosynostosis as a defining feature distinguishing SGS from other marfanoid conditions.


MONDO:0008426

[PMID:23103230] [SUPPORT] SGS is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. --- Explanation: Severe marfanoid habitus indicates disproportionate tall stature with long limbs as a key SGS feature.


MONDO:0008426

[PMID:24736733] [SUPPORT] A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. --- Explanation: Identifies intellectual disability as a distinguishing feature of SGS relative to MFS and LDS, though with variable penetrance.

[PMID:23103230] [SUPPORT] SGS is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. --- Explanation: Lists intellectual disability among the characteristic SGS features.


MONDO:0008426


MONDO:0008426

[PMID:23103230] [SUPPORT] SGS is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. --- Explanation: Lists camptodactyly (a form of flexion contracture) as a characteristic SGS feature.


MONDO:0008426

[PMID:23023332] [SUPPORT] Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS and LDS, including aortic aneurysm. --- Explanation: Identifies aortic aneurysm as a feature shared with MFS and LDS.


MONDO:0008426

[PMID:9508238] [SUPPORT] an abnormality of the first and second cervical vertebrae, hydrocephalus, dilatation of the lateral ventricles, and a Chiari-I malformation of the brain were found only in the patients with Shprintzen-Goldberg syndrome. --- Explanation: Cervical vertebral anomalies are a diagnostic radiologic finding specific to SGS among craniosynostosis-marfanoid disorders.


MONDO:0008426

[PMID:23023332] [INDIRECT EVIDENCE] [SUPPORT] Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-beta signaling cascades and higher expression of TGF-beta-responsive genes relative to control cells. --- Explanation: Direct evidence of enhanced TGF-beta signaling in patient-derived fibroblasts carrying SKI mutations.

[PMID:23023332] [INDIRECT EVIDENCE] [SUPPORT] These data support the conclusions that increased TGF-beta signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm. --- Explanation: Confirms that increased TGF-beta signaling is the primary pathogenic mechanism in SGS.

[PMID:23103230] [INDIRECT EVIDENCE] [SUPPORT] The interaction between SKI and Smad2/3 and Smad 4 regulates TGF-beta signaling, and the pattern of anomalies in Ski-deficient mice corresponds to the clinical manifestations of SGS. --- Explanation: Confirms SKI-SMAD interaction regulates TGF-beta signaling and that mouse models recapitulate the SGS phenotype.


MONDO:0008426

[PMID:24736733] [INDIRECT EVIDENCE] [SUPPORT] SGS is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys-Dietz syndrome (LDS). --- Explanation: Confirms SGS as a systemic connective tissue disorder with prominent skeletal manifestations.


HGNC.SYMBOL:SKI Mutations

[PMID:23023332] [SUPPORT] We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-beta activity. --- Explanation: Landmark paper identifying SKI as the causative gene for SGS in 10 patients.

[PMID:23103230] [SUPPORT] All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. --- Explanation: Confirms that SGS mutations cluster in the R-SMAD binding domain of SKI exon 1.

[PMID:24736733] [SUPPORT] 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). --- Explanation: Identifies a mutational hotspot in 5 SKI residues accounting for 73% of patients.


MONDO:0011382

[PMID:24277079] [PARTIAL] Heme rapidly (5 minutes) mobilized Weibel-Palade body (WPB) P-selectin and VWF onto EC and vessel wall surfaces and activated EC nuclear factor κB (NF-κB). --- Explanation: Heme-induced rapid release of adhesion molecules (P-selectin and von Willebrand factor) triggers vaso-occlusion, which causes pain crises in sickle cell disease.


MONDO:0011382

[PMID:15998894] [PARTIAL] hemolysis contributes to reduced nitric oxide bioavailability and endothelial dysfunction via release of erythrocyte arginase --- Explanation: Chronic hemolysis is a hallmark feature of sickle cell disease.


MONDO:0011382


MONDO:0011382

[PMID:24620350] [PARTIAL] Sickle cell disease (SCD) is characterized by recurring episodes of vascular occlusion in which neutrophil activation plays a major role. The disease is associated with chronic hemolysis with elevated cell-free hemoglobin and heme. --- Explanation: Neutrophil activation and hemolysis contribute to vascular occlusion and acute complications like acute chest syndrome.

[PMID:24620350] [PARTIAL] we have identified a novel role for heme in the induction of neutrophil extracellular trap (NET) formation in SCD. NETs are decondensed chromatin decorated by granular enzymes and are released by activated neutrophils. --- Explanation: Heme triggers neutrophil extracellular trap formation, which contributes to acute lung injury and acute chest syndrome in sickle cell disease.


MONDO:0011382

[PMID:29614632] [INDIRECT EVIDENCE] [PARTIAL] Due to the unique dependence of Hb S polymerization on cellular Hb S concentration, cell dehydration promotes polymerization and sickling. --- Explanation: HbS polymerization is concentration-dependent and leads to sickling.

[PMID:3965046] [INDIRECT EVIDENCE] [PARTIAL] Our results support the hypothesis that the intracellular polymerization of HbS is the primary determinant of the severity of both anemia and clinical symptomatology in the sickle hemoglobinopathies. --- Explanation: Establishes HbS polymerization as the primary determinant of clinical severity in sickling syndromes.


MONDO:0011382

[PMID:29614632] [INDIRECT EVIDENCE] [PARTIAL] In double heterozygosis for Hb S and C (SC disease) dehydration is the determining factor in disease pathophysiology. --- Explanation: Cell dehydration promotes sickling and fragility of red blood cells.


MONDO:0011382

[PMID:24277079] [INDIRECT EVIDENCE] [PARTIAL] intravascular hemolysis in SCD releases heme that activates endothelial TLR4 signaling leading to WPB degranulation, NF-κB activation, and vaso-occlusion. --- Explanation: Heme released from hemolysis triggers TLR4 signaling on endothelial cells, leading to Weibel-Palade body degranulation and release of P-selectin and von Willebrand factor, which promote adhesion and vaso-occlusion.


MONDO:0011382

[PMID:15998894] [INDIRECT EVIDENCE] [SUPPORT] hemolysis contributes to reduced nitric oxide bioavailability and endothelial dysfunction via release of erythrocyte arginase, which limits arginine bioavailability, and release of erythrocyte hemoglobin, which scavenges nitric oxide. --- Explanation: Hemolysis releases both arginase (which depletes L-arginine, the substrate for nitric oxide synthesis) and free hemoglobin (which directly scavenges nitric oxide), leading to endothelial dysfunction and pulmonary hypertension.

[PMID:15998894] [INDIRECT EVIDENCE] [PARTIAL] The ratios of arginine to ornithine and arginine to ornithine plus citrulline are independently associated with pulmonary hypertension and increased mortality in patients with sickle cell disease. --- Explanation: Low arginine bioavailability due to increased arginase activity is directly associated with pulmonary hypertension severity and mortality risk in SCD patients.


HGNC.SYMBOL:HBB

[PMID:18667698] [PARTIAL] Sickle cell disease (SCD) is a debilitating monogenic blood disorder with a highly variable phenotype characterized by severe pain crises, acute clinical events, and early mortality. --- Explanation: Confirms SCD is a monogenic blood disorder caused by HBB mutations.


HGNC.SYMBOL:BCL11A

[PMID:18667698] [SUPPORT] Common single nucleotide polymorphisms (SNPs) at the BCL11A and HBS1L-MYB loci have been implicated previously in HbF level variation --- Explanation: BCL11A polymorphisms regulate fetal hemoglobin levels and modify sickle cell disease severity.


HGNC.SYMBOL:HBS1L-MYB

[PMID:18667698] [SUPPORT] Together, common SNPs at the BCL11A, HBS1L-MYB, and beta-globin (HBB) loci account for >20% of the variation in HbF levels in SCD patients. --- Explanation: HBS1L-MYB locus polymorphisms are major modifiers of HbF levels in sickle cell disease.


MONDO:0019108

[PMID:8152774] [SUPPORT] Spontaneous enophthalmos and hypoglobus, in the absence of other symptoms and unrelated to trauma or surgery --- Explanation: The original 1994 paper describes spontaneous enophthalmos as the cardinal presenting feature, unrelated to trauma.

[PMID:23946747] [SUPPORT] The silent sinus syndrome (SSS) involves painless facial asymmetry and enophthalmos, which is the result of chronic maxillary sinus atelectasis. --- Explanation: Confirms enophthalmos as a defining feature of SSS.

[PMID:11404606] [SUPPORT] Four patients with enophthalmos and asymptomatic maxillary sinus disease were identified. --- Explanation: Case series confirms enophthalmos as the presenting feature with asymptomatic sinus disease.


MONDO:0019108

[PMID:23946747] [SUPPORT] The silent sinus syndrome (SSS) involves painless facial asymmetry and enophthalmos. --- Explanation: Facial asymmetry is listed as a defining clinical feature of SSS.


MONDO:0019108


MONDO:0019108

[PMID:23946747] [INDIRECT EVIDENCE] [SUPPORT] The silent sinus syndrome (SSS) involves painless facial asymmetry and enophthalmos, which is the result of chronic maxillary sinus atelectasis. --- Explanation: This reference directly states that SSS is the result of chronic maxillary sinus atelectasis, confirming the pathophysiological mechanism.

[PMID:11404606] [INDIRECT EVIDENCE] [SUPPORT] progressive enophthalmos secondary to maxillary collapse resulting from maxillary sinus hypoventilation --- Explanation: This reference describes the progressive collapse mechanism due to sinus hypoventilation.


MAXO:0035089

[PMID:23946747] [SUPPORT] Treatment involves functional endoscopic surgery. --- Explanation: FESS is identified as the primary treatment for SSS.

[PMID:11404606] [SUPPORT] All four underwent successful functional endoscopic sinus surgery and transconjunctival orbital floor repair. --- Explanation: Case series confirms successful treatment with functional endoscopic sinus surgery.


MAXO:0001292

[PMID:11404606] [SUPPORT] All four underwent successful functional endoscopic sinus surgery and transconjunctival orbital floor repair. --- Explanation: Transconjunctival orbital floor repair is described as part of the successful treatment approach.


MONDO:0010030

[PMID:38982205] [SUPPORT] Sjögren syndrome or Sjögren disease is a chronic form of autoimmune epithelitis characterized by lymphocytic infiltration of the exocrine glands, particularly the salivary and lacrimal glands, leading to progressive glandular dysfunction and subsequent xerostomia and xerophthalmia. --- Explanation: Xerostomia is listed as a primary clinical manifestation resulting from progressive salivary gland dysfunction in Sjögren's syndrome.


MONDO:0010030


MONDO:0010030

[PMID:38982205] [PARTIAL] Other common manifestations include pain and fatigue, various systemic manifestations and non-Hodgkin's lymphoma. --- Explanation: Fatigue is identified as a common manifestation in Sjögren's syndrome, highlighting its prominence among systemic symptoms.


MONDO:0010030

[PMID:33911236] [INDIRECT EVIDENCE] [SUPPORT] The ductal cells of the salivary gland in pSS are characteristically surrounded by a CD4+ T cell-rich and B cell-rich infiltrate, implying a degree of communication between epithelial cells and immune cells. --- Explanation: Demonstrates the characteristic lymphocytic infiltration pattern in salivary glands with both CD4+ T cells and B cells surrounding ductal epithelium.


MONDO:0010030

[PMID:38542233] [INDIRECT EVIDENCE] [PARTIAL] Primary Sjögren's disease is primarily driven by B-cell activation and is associated with a high risk of developing non-Hodgkin's lymphoma (NHL). --- Explanation: Highlights the central role of B-cell activation in primary Sjögren's disease, which drives autoantibody production including anti-Ro/SSA and anti-La/SSB antibodies.


MONDO:0010030

[PMID:33911236] [INDIRECT EVIDENCE] [PARTIAL] Multiple innate immune pathways are likely dysregulated in the salivary gland epithelium in pSS, including the nuclear factor-κB pathway, the inflammasome and interferon signalling. --- Explanation: Confirms that interferon signaling is a key dysregulated pathway in the salivary gland epithelium, contributing to the type I interferon signature observed in Sjögren's syndrome.

[PMID:38982205] [INDIRECT EVIDENCE] [PARTIAL] Several randomized controlled trials have just been completed or are poised to commence evaluating the effectiveness of novel drugs targeting both innate and adaptive immune pathways, including pro-inflammatory cytokines, the type I interferon system, B cell activation, B cell and T cell co-stimulation pathway, and ectopic germinal centre formation. --- Explanation: Highlights type I interferon system as a major therapeutic target in Sjögren's syndrome, underscoring its central pathogenic role.


MONDO:0010030

[PMID:33911236] [INDIRECT EVIDENCE] [PARTIAL] B cell infiltrates within the ducts can initiate the development of lymphoepithelial lesions, including basal ductal cell hyperplasia. Vice versa, the epithelium provides chronic activation signals to the glandular B cell fraction. --- Explanation: Demonstrates that epithelial cells actively participate in disease pathogenesis by providing chronic activation signals to immune cells, not merely serving as passive targets.

[PMID:38982205] [INDIRECT EVIDENCE] [PARTIAL] Sjögren syndrome or Sjögren disease is a chronic form of autoimmune epithelitis characterized by lymphocytic infiltration of the exocrine glands, particularly the salivary and lacrimal glands, leading to progressive glandular dysfunction and subsequent xerostomia and xerophthalmia. --- Explanation: Defines the disease as an autoimmune epithelitis, emphasizing the central role of epithelial cell dysfunction in disease pathology and clinical manifestations.


HGNC.SYMBOL:HLA-DR3


HGNC.SYMBOL:HLA-DQ2


HGNC.SYMBOL:IRF5


HGNC.SYMBOL:STAT4


MONDO:0011882

[PMID:11841538] [SUPPORT] electron microscopy demonstrated acantholysis throughout all layers of the skin, focal detachment of desmosomes into the intercellular spaces, and perinuclear condensation of the suprabasal keratin intermediate filament network --- Explanation: EM evidence of acantholysis and desmosome detachment directly demonstrates skin fragility at the ultrastructural level.


MONDO:0011882


MONDO:0011882

[PMID:11841538] [INDIRECT EVIDENCE] [SUPPORT] Mutation screening of desmoplakin demonstrated compound heterozygosity for a non-sense/mis-sense combination of mutations in both cases, C809X/N287K and Q664X/R2366C, respectively. --- Explanation: Identifies compound heterozygous DSP mutations as the molecular basis for skin fragility-woolly hair syndrome.

[PMID:11841538] [INDIRECT EVIDENCE] [SUPPORT] electron microscopy demonstrated acantholysis throughout all layers of the skin, focal detachment of desmosomes into the intercellular spaces, and perinuclear condensation of the suprabasal keratin intermediate filament network --- Explanation: Demonstrates the cellular pathology of desmosomal disruption in this condition.


MAXO:0000950


MAXO:0000079


hgnc:3052

[PMID:11841538] [SUPPORT] Heterozygous carriers of any of these mutations displayed no phenotypic abnormalities. --- Explanation: Confirms that haploinsufficiency alone is tolerated; compound heterozygosity is required for the skin fragility phenotype.

[PMID:11841538] [SUPPORT] desmoplakin haploinsufficiency can be tolerated in some cases, but that in combination with a mis-sense mutation on the other allele, the consequences are a severe genodermatosis with specific clinical manifestations --- Explanation: Establishes the genotype-phenotype correlation for compound heterozygosity.


MONDO:0008433


MONDO:0008433

[PMID:36399634] [INDIRECT EVIDENCE] [PARTIAL] The canonical model of "small cell lung cancer" (SCLC) depicts tumors arising from dual inactivation of TP53 and RB1. --- Explanation: Abstract states the canonical model involves TP53 and RB1 inactivation.


MONDO:0008433

[PMID:40931078] [INDIRECT EVIDENCE] [SUPPORT] Here we show that SCLC cells can form functional synapses and receive synaptic transmission. --- Explanation: Abstract reports functional synapses and synaptic transmission between neurons and SCLC cells.


MONDO:0008433

[PMID:40931078] [INDIRECT EVIDENCE] [SUPPORT] we showed that SCLC cells derive a proliferation advantage when co-cultured with vagal sensory or cortical neurons. --- Explanation: Abstract reports neuron co-culture provides a proliferation advantage to SCLC cells.


MONDO:0008433

[PMID:40931078] [INDIRECT EVIDENCE] [SUPPORT] Moreover, inhibition of glutamate signalling had therapeutic efficacy in an autochthonous mouse model of SCLC. --- Explanation: Abstract reports therapeutic efficacy of glutamate signaling inhibition in an SCLC mouse model.


MAXO:0000647


MAXO:0000058


NCIT:C106250


NCIT:C103194


MAXO:0000014


CHEBI:746908


CHEBI:63632


HGNC.SYMBOL:TP53


HGNC.SYMBOL:RB1


HGNC.SYMBOL:MYC


HGNC.SYMBOL:NOTCH


ECTO:6000029

[PMID:8166467] [SUPPORT] Cigarette smoking and occupational risk factors are more strongly associated with squamous and small cell lung cancers than with adenocarcinoma. --- Explanation: Supports the strong association between SCLC and cigarette smoking.


MONDO:0008433

[PMID:24734358] [SUPPORT] Small-cell lung cancer (SCLC) is a
very aggressive neuroendocrine carcinoma --- Explanation: Abstract defines SCLC as a very aggressive neuroendocrine carcinoma.


MONDO:0400000


MONDO:0400000

[PMID:38798120] [SUPPORT] is associated with diarrhea and signs of malabsorption --- Explanation: ESNM/ANMS update confirms diarrhea as a hallmark feature of SIBO.


MONDO:0400000

[PMID:38798120] [INDIRECT EVIDENCE] [SUPPORT] Small intestinal bacterial overgrowth (SIBO) has been recognized for over a century in patients with predisposing conditions causing intestinal stasis, such as surgical alteration of the small bowel or chronic diseases --- Explanation: ESNM/ANMS practice update confirms SIBO is well-established in stasis conditions.


MAXO:0000088


MONDO:0018669

[PMID:34430847] [SUPPORT] Generally, the main clinical features of snakebites are local swelling, tissue necrosis, shock, spontaneous systemic hemorrhage, incoagulable blood, paralysis, rhabdomyolysis, and acute kidney injury. --- Explanation: The abstract lists local swelling among clinical features.


MONDO:0018669

[PMID:34430847] [SUPPORT] Generally, the main clinical features of snakebites are local swelling, tissue necrosis, shock, spontaneous systemic hemorrhage, incoagulable blood, paralysis, rhabdomyolysis, and acute kidney injury. --- Explanation: The abstract lists systemic hemorrhage and incoagulable blood.


MONDO:0018669

[PMID:34430847] [SUPPORT] Generally, the main clinical features of snakebites are local swelling, tissue necrosis, shock, spontaneous systemic hemorrhage, incoagulable blood, paralysis, rhabdomyolysis, and acute kidney injury. --- Explanation: The abstract lists paralysis among clinical features.


MONDO:0018669

[PMID:34430847] [SUPPORT] Generally, the main clinical features of snakebites are local swelling, tissue necrosis, shock, spontaneous systemic hemorrhage, incoagulable blood, paralysis, rhabdomyolysis, and acute kidney injury. --- Explanation: The abstract lists acute kidney injury among clinical features.


MAXO:0000058

[PMID:28905944] [SUPPORT] Intravenous administration of antivenom is the only specific treatment to counteract envenoming. --- Explanation: The abstract states antivenom is the only specific treatment.


MONDO:0004664

[PMID:27929101] [PARTIAL] Adult worms feed on the blood of a host and can cause iron deficiency anaemia --- Explanation: Iron deficiency anemia is a consequence of hookworm infection.


MAXO:0000058

[PMID:16679166] [SUPPORT] The benzimidazole anthelmintics, mebendazole and albendazole, are commonly used to remove these infections. --- Explanation: Albendazole and mebendazole are standard anthelmintic therapies.


CHEBI:16664

[PMID:16679166] [INDIRECT EVIDENCE] [SUPPORT] The benzimidazole anthelmintics, mebendazole and albendazole, are commonly used to remove these infections. --- Explanation: Albendazole and mebendazole are standard anthelmintic therapies.


NCBITaxon:6252

[PMID:28882382] [SUPPORT] soil-transmitted helminths Ascaris lumbricoides, hookworm (Ancylostoma duodenale and Necator americanus), Trichuris trichiura, and Strongyloides stercoralis --- Explanation: The review lists Ascaris lumbricoides among soil-transmitted helminths.


NCBITaxon:36087

[PMID:28882382] [SUPPORT] soil-transmitted helminths Ascaris lumbricoides, hookworm (Ancylostoma duodenale and Necator americanus), Trichuris trichiura, and Strongyloides stercoralis --- Explanation: The review lists Trichuris trichiura among soil-transmitted helminths.


NCBITaxon:51022

[PMID:28882382] [SUPPORT] soil-transmitted helminths Ascaris lumbricoides, hookworm (Ancylostoma duodenale and Necator americanus), Trichuris trichiura, and Strongyloides stercoralis --- Explanation: The review lists Ancylostoma duodenale as a hookworm species.


NCBITaxon:51031

[PMID:28882382] [SUPPORT] soil-transmitted helminths Ascaris lumbricoides, hookworm (Ancylostoma duodenale and Necator americanus), Trichuris trichiura, and Strongyloides stercoralis --- Explanation: The review lists Necator americanus as a hookworm species.


NCBITaxon:6248

[PMID:28882382] [SUPPORT] soil-transmitted helminths Ascaris lumbricoides, hookworm (Ancylostoma duodenale and Necator americanus), Trichuris trichiura, and Strongyloides stercoralis --- Explanation: The review lists Strongyloides stercoralis among soil-transmitted helminths.


MONDO:0001516

[PMID:18572081] [SUPPORT] Spinal muscular atrophy is an autosomal recessive neurodegenerative disease characterised by degeneration of spinal cord motor neurons, atrophy of skeletal muscles, and generalised weakness. --- Explanation: Lancet review confirms generalized weakness as a characteristic of SMA, presenting as hypotonia in infants.


MONDO:0001516

[PMID:16364894] [SUPPORT] The disease results in motor neuron loss and skeletal muscle atrophy. --- Explanation: Review confirms skeletal muscle atrophy (weakness) as a direct result of motor neuron loss in SMA.


MONDO:0001516

[PMID:18572081] [SUPPORT] Spinal muscular atrophy is an autosomal recessive neurodegenerative disease characterised by degeneration of spinal cord motor neurons, atrophy of skeletal muscles, and generalised weakness. --- Explanation: Motor neuron degeneration leads to loss of deep tendon reflexes (areflexia).


MONDO:0001516


MONDO:0001516

[PMID:29091570] [SUPPORT] the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). --- Explanation: ENDEAR trial uses permanent assisted ventilation as a primary endpoint, confirming respiratory failure as a key clinical outcome in infantile SMA.


MONDO:0001516

[PMID:16364894] [SUPPORT] The disease results in motor neuron loss and skeletal muscle atrophy. --- Explanation: Progressive muscle weakness including paraspinal muscles leads to scoliosis in SMA patients.


MONDO:0001516

[PMID:16364894] [INDIRECT EVIDENCE] [SUPPORT] SMA is caused by mutations in a single gene, the Survival of Motor Neuron 1 (SMN1) gene. --- Explanation: Review confirms SMN1 gene mutations cause SMA.

[PMID:18572081] [INDIRECT EVIDENCE] [SUPPORT] Spinal muscular atrophy is an autosomal recessive neurodegenerative disease characterised by degeneration of spinal cord motor neurons, atrophy of skeletal muscles, and generalised weakness. It is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene by deletion, conversion, or mutation. --- Explanation: Lancet review confirms SMN1 gene disruption causes SMA with motor neuron degeneration.


MONDO:0001516

[PMID:16364894] [INDIRECT EVIDENCE] [SUPPORT] The disease results in motor neuron loss and skeletal muscle atrophy. --- Explanation: Review confirms motor neuron loss as the pathological basis of SMA.


HGNC.SYMBOL:SMN1

[PMID:18572081] [SUPPORT] It is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene by deletion, conversion, or mutation. --- Explanation: Lancet review confirms SMN1 gene disruption is the causative mechanism of SMA.


HGNC.SYMBOL:SMN2


MONDO:0010094

[PMID:29566257] [SUPPORT] Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones. --- Explanation: This directly supports disproportionate short stature.


MONDO:0010094

[PMID:17635842] [SUPPORT] Spondylocarpotarsal synostosis syndrome (SCT) is an autosomal recessive disease that is characterized by short stature, and fusions of the vertebrae and carpal and tarsal bones. --- Explanation: This directly supports vertebral fusion in the human disease phenotype.


MONDO:0010094

[PMID:29566257] [SUPPORT] Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones. --- Explanation: This supports carpal fusion/synostosis as a core phenotype.


MONDO:0010094

[PMID:29566257] [SUPPORT] Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones. --- Explanation: This directly supports tarsal synostosis.


MONDO:0010094

[PMID:28145000] [SUPPORT] Spondylocarpotarsal synostosis syndrome (SCT) is a distinct group of disorders characterized by short stature, disrupted vertebral segmentation with vertebral fusion, scoliosis, lordosis, carpal/tarsal synostosis, and lack of rib anomalies. --- Explanation: This directly supports scoliosis as a core clinical feature.


MONDO:0010094

[PMID:28145000] [SUPPORT] Spondylocarpotarsal synostosis syndrome (SCT) is a distinct group of disorders characterized by short stature, disrupted vertebral segmentation with vertebral fusion, scoliosis, lordosis, carpal/tarsal synostosis, and lack of rib anomalies. --- Explanation: This supports lordotic spinal deformity in SCTSS.


MONDO:0010094

[PMID:39086440] [SUPPORT] Other findings included clinodactyly, joint limitation without bone fusion, neurosensorial hearing loss, and ophthalmological compromise. --- Explanation: This supports variable sensorineural hearing involvement in SCTSS.


MONDO:0010094

[PMID:17635842] [INDIRECT EVIDENCE] [SUPPORT] Protein extracts derived from cells of SCT patients with nonsense mutations in FLNB did not contain filamin B, demonstrating that SCT results from absence of filamin B. --- Explanation: This directly links SCT pathogenesis to filamin B deficiency from FLNB truncating variants.

[PMID:29566257] [INDIRECT EVIDENCE] [SUPPORT] Biallelic loss-of-function variants in FLNB are known to cause spondylocarpotarsal synostosis syndrome and 9 families and 9 pathogenic variants have been reported so far. --- Explanation: This supports loss-of-function FLNB as the established molecular mechanism.


MONDO:0010094


MONDO:0010094

[PMID:28145000] [INDIRECT EVIDENCE] [SUPPORT] The mutant p.S2542Lfs* 82 FLNB demonstrated a complete loss of ability to form a functional dimer in transiently transfected HEK293T cells. --- Explanation: This provides direct in vitro evidence of impaired FLNB dimerization.

[PMID:28145000] [INDIRECT EVIDENCE] [SUPPORT] The p.S2542Lfs* 82 mutation also led to significantly reduced protein levels and accumulation of the mutant protein in the Golgi apparatus. --- Explanation: This supports decreased FLNB protein stability and mislocalization.


MONDO:0010094

[PMID:17635842] [INDIRECT EVIDENCE] [SUPPORT] Analysis of the Flnb-/- mice phenotype showed that an absence of filamin B causes progressive vertebral fusions, which is contrary to the previous hypothesis that SCT results from failure of normal spinal segmentation. --- Explanation: This supports progressive fusion as a key disease process in FLNB deficiency.

[PMID:17635842] [INDIRECT EVIDENCE] [SUPPORT] These findings suggest that spinal segmentation can occur normally in the absence of filamin B, but the protein is required for maintenance of intervertebral, carpal and sternal joints, and the joint fusion process commences antenatally. --- Explanation: This supports a joint-maintenance failure mechanism with early fusion onset.


hgnc:3755

[PMID:17635842] [SUPPORT] SCT results from homozygosity or compound heterozygosity for nonsense mutations in FLNB. --- Explanation: This directly supports biallelic FLNB nonsense variants as causative.

[PMID:29566257] [SUPPORT] Our report validates key clinical (fused thoracic vertebrae and carpal and tarsal coalition) and molecular (truncating variants in FLNB) characteristics of this condition. --- Explanation: This supports truncating FLNB variants as a defining molecular feature.

[PMID:39086440] [SUPPORT] Three different FLNB variants, one nonsense and two frameshift, were detected, all of which were predicted to result in a truncated protein or are degraded by nonsense mediated decay. --- Explanation: This provides additional cohort-level evidence for truncating biallelic FLNB variants.


MONDO:0010094

[PMID:33407338] [SUPPORT] BACKGROUND: Loss of function or gain of function variants of Filamin B (FLNB) cause recessive or dominant skeletal disorders respectively. Spondylocarpotarsal synostosis syndrome (SCT) is a rare autosomal recessive disorder characterized by short stature, fused vertebrae and fusion of carpal and tarsal bones. --- Explanation: This directly supports recessive inheritance and the core autosomal recessive SCT phenotype.

[PMID:17635842] [SUPPORT] Spondylocarpotarsal synostosis syndrome (SCT) is an autosomal recessive disease that is characterized by short stature, and fusions of the vertebrae and carpal and tarsal bones. --- Explanation: This independently supports autosomal recessive inheritance and hallmark clinical features.


MONDO:0007526

[PMID:28882145] [SUPPORT] The majority of spEDS patients presented with short stature, skin hyperextensibility, facial dysmorphisms, peculiar radiological findings, muscle hypotonia and joint laxity --- Explanation: Short stature is listed as a major feature of spEDS.

[PMID:32295219] [SUPPORT] significant short stature of childhood onset --- Explanation: Short stature confirmed in SLC39A13-spEDS patients.


MONDO:0007526

[PMID:28882145] [SUPPORT] The majority of spEDS patients presented with short stature, skin hyperextensibility, facial dysmorphisms, peculiar radiological findings, muscle hypotonia and joint laxity --- Explanation: Muscle hypotonia is a major feature of spEDS.

[PMID:38609428] [SUPPORT] patients with EDSSPD3 harboring a homozygous loss of function mutation (c.221G > A, p.G64D) in ZIP13 exon 2 (ZIP13G64D) suffer from impaired development of bone and connective tissues, and muscular hypotonia --- Explanation: Muscular hypotonia confirmed as a feature of SLC39A13-spEDS.


MONDO:0007526

[PMID:32295219] [SUPPORT] platyspondyly is a useful diagnostic feature --- Explanation: Platyspondyly is highlighted as a diagnostically useful radiographic finding.


MONDO:0007526

[PMID:28882145] [SUPPORT] The majority of spEDS patients presented with short stature, skin hyperextensibility, facial dysmorphisms, peculiar radiological findings, muscle hypotonia and joint laxity --- Explanation: Skin hyperextensibility listed as a feature of spEDS.


MONDO:0007526

[PMID:36756177] [SUPPORT] We noted a high prevalence of joint hypermobility amongst kyphoscoliotic (39/39, 100%), spondylodysplastic (24/25, 96.0%), and hypermobile (153/160, 95.6%) EDS subtypes --- Explanation: Systematic review quantifying 96% prevalence of joint hypermobility in spEDS.

[PMID:28882145] [SUPPORT] The majority of spEDS patients presented with short stature, skin hyperextensibility, facial dysmorphisms, peculiar radiological findings, muscle hypotonia and joint laxity --- Explanation: Joint laxity confirmed as a common feature of spEDS.


MONDO:0007526

[PMID:34193099] [SUPPORT] skin hyperextensibility, soft doughy skin, pes planus, delayed motor and cognitive development and osteopenia as minor criteria --- Explanation: Osteopenia listed among minor diagnostic criteria.


MONDO:0007526

[PMID:31862401] [SUPPORT] Morphant and crispant zebrafish show highly similar morphological abnormalities in early development including a small, round head, bowed pectoral fins, short body-axis and mild developmental delay --- Explanation: Zebrafish models of B4galt7 deficiency show bowed pectoral fins, recapitulating the limb bowing phenotype seen in human spEDS.


MONDO:0007526

[PMID:34193099] [SUPPORT] skin hyperextensibility, soft doughy skin, pes planus, delayed motor and cognitive development and osteopenia as minor criteria --- Explanation: Pes planus listed as a minor criterion.


MONDO:0007526

[PMID:28882145] [SUPPORT] in addition to short stature and muscle hypotonia, radioulnar synostosis, hypermetropia, and delayed cognitive development might be a hallmark of this specific type of spEDS --- Explanation: Radioulnar synostosis is a hallmark finding in B4GALT7-spEDS.


MONDO:0007526

[PMID:32295219] [SUPPORT] thin and finely wrinkled skin of the hands and feet, characteristic facial features with downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish sclerae --- Explanation: Bluish sclerae described as a characteristic feature in SLC39A13-spEDS.


MONDO:0007526

[PMID:32295219] [SUPPORT] characteristic facial features with downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish sclerae --- Explanation: Downslanting palpebral fissures are a characteristic facial feature.


MONDO:0007526

[PMID:32295219] [SUPPORT] prominent eyes with a paucity of periorbital fat --- Explanation: Prominent eyes described in SLC39A13-spEDS facial gestalt.


MONDO:0007526

[PMID:32295219] [SUPPORT] thin and finely wrinkled skin of the hands and feet --- Explanation: Thin wrinkled acral skin is a distinguishing feature of SLC39A13-spEDS.


MONDO:0007526

[PMID:32295219] [SUPPORT] Two of our patients developed severe keratoconus --- Explanation: Keratoconus reported as a complication in adult SLC39A13-spEDS patients.


MONDO:0007526

[PMID:32295219] [SUPPORT] mild hypertelorism --- Explanation: Mild hypertelorism noted as part of characteristic facial features.


MONDO:0007526

[PMID:32295219] [SUPPORT] microdontia, or oligodontia --- Explanation: Oligodontia is part of the dental phenotype in SLC39A13-spEDS.


MONDO:0007526

[PMID:34193099] [INDIRECT EVIDENCE] [SUPPORT] galactosyltransferase I, which is required for the initiation of glycosaminoglycan side chain synthesis of proteoglycans --- Explanation: Describes the enzymatic role of B4GALT7 in initiating GAG chain synthesis.

[PMID:34807422] [INDIRECT EVIDENCE] [SUPPORT] Spondylodysplastic EDS is caused by pathogenic variants in B4GALT7 or B3GALT6, both of which encode key enzymes that initiate glycosaminoglycan synthesis --- Explanation: Confirms that both B4GALT7 and B3GALT6 are involved in GAG biosynthesis initiation.

[PMID:36101818] [INDIRECT EVIDENCE] [SUPPORT] contained two different glycopeptide peaks, corresponding to the canonical tetrasaccharide and to the non-canonical trisaccharide linkage region modifications --- Explanation: Demonstrates abnormal GAG linkage region structure in B3GALT6 deficiency.


MONDO:0007526


MONDO:0007526

[PMID:39738060] [INDIRECT EVIDENCE] [SUPPORT] ZIP13 loss causes an iron deficiency in the ER/Golgi and other intracellular compartments, such as lysosomes and mitochondria, as well as elevating iron in the cytosol --- Explanation: Demonstrates that ZIP13 functions as an iron transporter supplying the ER/Golgi, redefining the molecular mechanism of SLC39A13-spEDS.


hgnc:930

[PMID:34193099] [SUPPORT] galactosyltransferase I, which is required for the initiation of glycosaminoglycan side chain synthesis of proteoglycans --- Explanation: Describes B4GALT7 enzymatic function and its link to spEDS.

[PMID:28882145] [SUPPORT] Spondylodysplastic EDS (spEDS) is a rare connective tissue disorder that groups the phenotypes caused by biallelic B4GALT7, B3GALT6, and SLC39A13 mutations --- Explanation: Confirms B4GALT7 as one of three causative genes for spEDS.


hgnc:17978

[PMID:37657630] [SUPPORT] each 'linker' gene encodes an enzyme responsible for the addition of glycosaminoglycan chains to proteoglycans via a common tertrasaccharine linker region --- Explanation: Establishes B3GALT6 as a linker gene causing a linkeropathy classified under spEDS.

[PMID:34159694] [SUPPORT] Beta3GalT6-related disorders were grouped in the spondylodysplastic EDSs together with spondylodysplastic EDSs due to B4GALT7 and SLC39A13 mutations --- Explanation: Confirms B3GALT6-related disorders are classified under spEDS.


hgnc:20859

[PMID:32295219] [SUPPORT] Recessive loss-of-function variants in SLC39A13, a putative zinc transporter gene, were first associated with a connective tissue disorder --- Explanation: Identifies SLC39A13 as a causative gene for spEDS via zinc transport deficiency.

[PMID:36727144] [SUPPORT] a novel mutation in SLC39A13 causing spondylodysplastic Ehlers-Danlos syndrome --- Explanation: Case report confirming a novel SLC39A13 variant causing spEDS.


MONDO:0007526

[PMID:28882145] [SUPPORT] Spondylodysplastic EDS (spEDS) is a rare connective tissue disorder that groups the phenotypes caused by biallelic B4GALT7, B3GALT6, and SLC39A13 mutations --- Explanation: Confirms biallelic (autosomal recessive) inheritance for spEDS.

[PMID:32295219] [SUPPORT] Recessive loss-of-function variants in SLC39A13, a putative zinc transporter gene, were first associated with a connective tissue disorder --- Explanation: Confirms recessive inheritance for SLC39A13-spEDS.


MONDO:0008476

[PMID:7550321] [SUPPORT] The Strudwick type of spondyloepimetaphyseal dysplasia (SEMD) is characterized by disproportionate short stature, pectus carinatum, and scoliosis, as well as dappled metaphyses (which are not seen in SEDC). --- Explanation: Disproportionate short stature is one of the defining features of SEMD Strudwick.


MONDO:0008476

[PMID:7550321] [SUPPORT] The Strudwick type of spondyloepimetaphyseal dysplasia (SEMD) is characterized by disproportionate short stature, pectus carinatum, and scoliosis, as well as dappled metaphyses (which are not seen in SEDC). --- Explanation: Scoliosis is one of the characteristic features of SEMD Strudwick.


MONDO:0008476

[PMID:16280719] [SUPPORT] The orthopaedic manifestations of patients can be hypoplastic odontoid peg with atlantoaxial instability, severe kyphosis or lordosis of dorsal and lumbar spines, hip subluxation, coxa vara and early severe hip osteoarthritis, and malalignment of lower limbs like genu valgum or club foot. --- Explanation: Severe kyphosis documented as an orthopaedic manifestation of SEMD Strudwick.


MONDO:0008476

[PMID:16280719] [SUPPORT] The orthopaedic manifestations of patients can be hypoplastic odontoid peg with atlantoaxial instability, severe kyphosis or lordosis of dorsal and lumbar spines, hip subluxation, coxa vara and early severe hip osteoarthritis, and malalignment of lower limbs like genu valgum or club foot. --- Explanation: Lordosis of dorsal and lumbar spines documented in SEMD Strudwick patients.


MONDO:0008476

[PMID:7550321] [SUPPORT] The Strudwick type of spondyloepimetaphyseal dysplasia (SEMD) is characterized by disproportionate short stature, pectus carinatum, and scoliosis, as well as dappled metaphyses (which are not seen in SEDC). --- Explanation: Pectus carinatum is a characteristic feature of SEMD Strudwick.


MONDO:0008476

[PMID:18328979] [SUPPORT] The spondylo-epi-metaphyseal dysplasias (SEMD) are a heterogeneous group of disorders comprising more than 20 distinct entities with differing modes of inheritance, all defined by the combination of vertebral, epiphyseal and metaphyseal abnormalities. --- Explanation: Vertebral abnormalities (including platyspondyly) are a defining component of the SEMD group.


MONDO:0008476

[PMID:7550321] [SUPPORT] The Strudwick type of spondyloepimetaphyseal dysplasia (SEMD) is characterized by disproportionate short stature, pectus carinatum, and scoliosis, as well as dappled metaphyses (which are not seen in SEDC). --- Explanation: Dappled metaphyses are the key distinguishing feature of SEMD Strudwick versus SEDC.

[PMID:17163530] [SUPPORT] A mild degree of metaphyseal dysplasia can be seen in the so-called Strudwick variant of spondyloepimetaphyseal dysplasia and is generally mild or absent in other forms. --- Explanation: Confirms metaphyseal dysplasia as a defining feature of the Strudwick variant of SEMD.


MONDO:0008476

[PMID:18328979] [SUPPORT] epiphyseal dysplasia is often a predominant feature, and the course of the disease is marked by premature osteoarthritis --- Explanation: Epiphyseal dysplasia is identified as a predominant feature in SEMD disorders.


MONDO:0008476

[PMID:16280719] [SUPPORT] The orthopaedic manifestations of patients can be hypoplastic odontoid peg with atlantoaxial instability, severe kyphosis or lordosis of dorsal and lumbar spines, hip subluxation, coxa vara and early severe hip osteoarthritis, and malalignment of lower limbs like genu valgum or club foot. --- Explanation: Coxa vara documented as an orthopaedic manifestation in SEMD Strudwick.


MONDO:0008476

[PMID:16280719] [SUPPORT] The orthopaedic manifestations of patients can be hypoplastic odontoid peg with atlantoaxial instability, severe kyphosis or lordosis of dorsal and lumbar spines, hip subluxation, coxa vara and early severe hip osteoarthritis, and malalignment of lower limbs like genu valgum or club foot. --- Explanation: Genu valgum documented as a lower limb malalignment manifestation in SEMD Strudwick.


MONDO:0008476

[PMID:16280719] [SUPPORT] The orthopaedic manifestations of patients can be hypoplastic odontoid peg with atlantoaxial instability, severe kyphosis or lordosis of dorsal and lumbar spines, hip subluxation, coxa vara and early severe hip osteoarthritis, and malalignment of lower limbs like genu valgum or club foot. --- Explanation: Atlantoaxial instability with hypoplastic odontoid peg documented in SEMD Strudwick patients.

[PMID:18328979] [SUPPORT] A systematic survey of odontoid hypoplasia responsible for atlantoaxial instability with a risk of spinal cord is also required. --- Explanation: Review highlights the importance of systematic surveillance for odontoid hypoplasia and atlantoaxial instability in SEMD.

[PMID:25604898] [SUPPORT] Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available --- Explanation: Quantifies atlantoaxial instability at 28% in the subset of COL2A1 patients with appropriate imaging.


MONDO:0008476

[PMID:16280719] [SUPPORT] The orthopaedic manifestations of patients can be hypoplastic odontoid peg with atlantoaxial instability, severe kyphosis or lordosis of dorsal and lumbar spines, hip subluxation, coxa vara and early severe hip osteoarthritis, and malalignment of lower limbs like genu valgum or club foot. --- Explanation: Hypoplastic odontoid peg documented as an orthopaedic manifestation in SEMD Strudwick.

[PMID:25604898] [SUPPORT] Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. --- Explanation: Quantifies odontoid hypoplasia at 56% in a large COL2A1 cohort with correlation to short stature.


MONDO:0008476


MONDO:0008476

[PMID:12925722] [SUPPORT] the autosomal dominant Strudwick-type SEMD in a three-generation family, showing specific phenotypical features such as chest deformity, limb shortening, myopia and early-onset degenerative osteoarthrosis --- Explanation: Myopia documented as a specific phenotypical feature in a three-generation family.

[PMID:25604898] [SUPPORT] Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). --- Explanation: Large COL2A1 cohort including SEMD patients quantifies myopia frequency at 45%.


MONDO:0008476

[PMID:25604898] [SUPPORT] Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). --- Explanation: Large COL2A1 cohort including SEMD patients quantifies retinal detachment at 12%, with earliest case at 3.5 years.


MONDO:0008476

[PMID:25604898] [SUPPORT] Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. --- Explanation: Large COL2A1 cohort including SEMD patients quantifies hearing loss at 37%.


MONDO:0008476

[PMID:12925722] [SUPPORT] the autosomal dominant Strudwick-type SEMD in a three-generation family, showing specific phenotypical features such as chest deformity, limb shortening, myopia and early-onset degenerative osteoarthrosis --- Explanation: Early-onset degenerative osteoarthrosis documented as a specific phenotypical feature.

[PMID:16280719] [SUPPORT] The orthopaedic manifestations of patients can be hypoplastic odontoid peg with atlantoaxial instability, severe kyphosis or lordosis of dorsal and lumbar spines, hip subluxation, coxa vara and early severe hip osteoarthritis, and malalignment of lower limbs like genu valgum or club foot. --- Explanation: Early severe hip osteoarthritis documented with 30-year follow-up.

[PMID:18328979] [SUPPORT] epiphyseal dysplasia is often a predominant feature, and the course of the disease is marked by premature osteoarthritis --- Explanation: Review confirms premature osteoarthritis marks the disease course across SEMD disorders.


MONDO:0008476

[PMID:16280719] [SUPPORT] The orthopaedic manifestations of patients can be hypoplastic odontoid peg with atlantoaxial instability, severe kyphosis or lordosis of dorsal and lumbar spines, hip subluxation, coxa vara and early severe hip osteoarthritis, and malalignment of lower limbs like genu valgum or club foot. --- Explanation: Hip subluxation documented as an orthopaedic manifestation in SEMD Strudwick.


MONDO:0008476

[PMID:16280719] [SUPPORT] The orthopaedic manifestations of patients can be hypoplastic odontoid peg with atlantoaxial instability, severe kyphosis or lordosis of dorsal and lumbar spines, hip subluxation, coxa vara and early severe hip osteoarthritis, and malalignment of lower limbs like genu valgum or club foot. --- Explanation: Club foot documented as a lower limb malalignment manifestation in SEMD Strudwick.


MONDO:0008476

[PMID:7550321] [INDIRECT EVIDENCE] [SUPPORT] We now describe the biochemical characterization of defects in alpha 1(II) collagen in three unrelated individuals with SEMD Strudwick, each of which is due to heterozygosity for a unique mutation in COL2A1. --- Explanation: Biochemical characterization in three unrelated SEMD Strudwick patients established that heterozygous COL2A1 mutations produce abnormal alpha-1(II) collagen chains.

[PMID:12925722] [INDIRECT EVIDENCE] [SUPPORT] All previously reported autosomal dominant mutations causing SEMD have substituted an obligate glycine within the triple helix, in particular at codons 292, 304 and 709 in the three reported Strudwick-type patients. --- Explanation: Documents that all known SEMD Strudwick mutations substitute glycine residues within the triple helix, confirming the dominant-negative mechanism.

[PMID:26443184] [INDIRECT EVIDENCE] [SUPPORT] One-third of the mutations are dominant-negative mutations that affect the glycine residue in the G-X-Y repeats of the alpha 1 chain. These mutations disrupt the collagen triple helix and are common in achondrogenesis type II and hypochondrogenesis. --- Explanation: Comprehensive review of 415 COL2A1 mutations confirms that glycine substitutions in the Gly-X-Y repeats produce dominant-negative effects disrupting the triple helix.


MONDO:0008476

[PMID:25451152] [INDIRECT EVIDENCE] [SUPPORT] Our studies demonstrated that chondrocytes expressing the thermolabile R992C mutant collagen II molecules endured endoplasmic reticulum stress, had atypical polarization, and had reduced proliferation. --- Explanation: Conditional transgenic mouse model of SED demonstrates ER stress, atypical chondrocyte polarization, and reduced proliferation as direct consequences of mutant collagen II expression.

[PMID:25187577] [INDIRECT EVIDENCE] [SUPPORT] The COL2pathy-iChon cells showed suppressed expression of COL2A1 and significant apoptosis. A distended endoplasmic reticulum (ER) was detected, thus suggesting the adaptation of gene expression and cell death caused by excess ER stress. --- Explanation: Patient-derived iPSC chondrocytes demonstrate ER distension, suppressed COL2A1 expression, and apoptosis, directly modeling the ER stress pathomechanism.

[PMID:40602718] [INDIRECT EVIDENCE] [SUPPORT] Arg719Cys procollagen-II was excessively post-translationally modified and partially retained within the endoplasmic reticulum (ER), leading to ER distention. Notably, despite introduction of an aberrant cysteine residue-expected to engage redox-sensitive folding and quality control pathways-Arg719Cys procollagen-II was not detectably recognized by the ER proteostasis network. --- Explanation: Demonstrates that certain COL2A1 substitutions cause ER retention and matrix deficiency without canonical UPR activation, revealing a failed surveillance mechanism.


MONDO:0008476

[PMID:25451152] [INDIRECT EVIDENCE] [SUPPORT] we analyzed the pathomechanisms responsible for growth alterations in transgenic mice with conditional expression of the R992C collagen II mutation. Specifically, we studied the alterations of the growth plates of mutant mice in which chondrocytes lacked their typical columnar arrangement. --- Explanation: Directly demonstrates that mutant collagen II expression disrupts growth plate columnar organization, a hallmark of impaired endochondral ossification.

[PMID:7550321] [INDIRECT EVIDENCE] [SUPPORT] Individuals affected with these disorders exhibit abnormalities of the growth plate, nucleus pulposus, and vitreous humor, which are tissues that contain type II collagen. --- Explanation: Growth plate abnormalities in SEMD Strudwick patients confirm disrupted endochondral ossification in human disease.


MONDO:0008476

[PMID:18328979] [INDIRECT EVIDENCE] [SUPPORT] epiphyseal dysplasia is often a predominant feature, and the course of the disease is marked by premature osteoarthritis --- Explanation: Review of SEMD disorders confirms premature osteoarthritis as a hallmark complication related to epiphyseal cartilage defects.

[PMID:12925722] [INDIRECT EVIDENCE] [SUPPORT] the autosomal dominant Strudwick-type SEMD in a three-generation family, showing specific phenotypical features such as chest deformity, limb shortening, myopia and early-onset degenerative osteoarthrosis --- Explanation: Early-onset degenerative osteoarthrosis documented in a three-generation Strudwick family reflects the defective articular cartilage matrix.


MAXO:0000004

[PMID:16280719] [SUPPORT] We report a mother and daughter with SEMD Strudwick Type and describe their orthopaedic problems, surgical management and clinical outcome after 30 years and 7 years of follow-up respectively. --- Explanation: Long-term follow-up documents the orthopedic surgical interventions required in SEMD Strudwick patients.

[PMID:25604898] [SUPPORT] Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. --- Explanation: Large cohort demonstrates that over half of COL2A1 patients require orthopedic surgery.


MAXO:0000482


MAXO:0000004


hgnc:2200

[PMID:7550321] [SUPPORT] We now describe the biochemical characterization of defects in alpha 1(II) collagen in three unrelated individuals with SEMD Strudwick, each of which is due to heterozygosity for a unique mutation in COL2A1. --- Explanation: Landmark paper establishing that heterozygous COL2A1 mutations cause SEMD Strudwick through biochemical characterization in three unrelated patients.

[PMID:12925722] [SUPPORT] A point mutation within exon 20 of the COL2A1 gene was identified that substituted a glycine for an aspartic acid residue at codon 262. --- Explanation: Identifies a novel Gly262Asp mutation in a three-generation family, extending the mutational spectrum.

[PMID:26443184] [SUPPORT] Over 700 patients were recorded, harboring 415 different mutations. One-third of the mutations are dominant-negative mutations that affect the glycine residue in the G-X-Y repeats of the alpha 1 chain. --- Explanation: Comprehensive mutation database review establishes glycine substitutions as the major class of dominant-negative COL2A1 mutations across type II collagenopathies.

[PMID:17163530] [SUPPORT] One patient who carried a Gly283Arg substitution had a pattern of metaphyseal dysplasia that corresponded precisely to what was termed 'Murdoch type metaphyseal dysplasia' in 1960s and was renamed Strudwick type SEMD in 1980s. --- Explanation: Identifies Gly283Arg as another glycine substitution producing the Strudwick pattern of metaphyseal dysplasia.


MONDO:0008471

[PMID:1971141] [SUPPORT] Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominantly inherited chondrodysplasia characterized by disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. --- Explanation: Disproportionate short-trunk short stature is a defining diagnostic criterion for SEDC.

[PMID:31824186] [SUPPORT] SEDC is a rare disease with a prevalence of 3.4/1,000,000. At birth patients with SEDC are short (mean length 45 cm at term) with flattened vertebras --- Explanation: Provides quantitative birth length data for SEDC.


MONDO:0008471

[PMID:1971141] [SUPPORT] Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominantly inherited chondrodysplasia characterized by disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. --- Explanation: Flattened vertebral bodies (platyspondyly) is identified as a defining characteristic of SEDC.


MONDO:0008471

[PMID:31824186] [SUPPORT] Adult patients also show flat face for skeletal hypoplasia with prominent eyes and cleft palate, barrel-chest and pectus carinatum. --- Explanation: Review documenting flat face as a characteristic feature of SEDC adults.


MONDO:0008471

[PMID:11878179] [SUPPORT] Cleft palate is one of the common features of spondyloepiphyseal dysplasia congenita (SEDC). However, there are few clinical data about cleft palate in SEDC. We report four patients with cleft palate and SEDC including two with overt cleft palate and two with submucous cleft palate. --- Explanation: Case series documenting cleft palate as a common feature of SEDC and noting that submucous cleft palate may be more common than previously appreciated.

[PMID:35581182] [SUPPORT] extraskeletal features, including myopia, retinal degeneration with retinal detachment, and cleft palate --- Explanation: Recent series confirming cleft palate among the extraskeletal features of SEDC.


MONDO:0008471

[PMID:6807266] [SUPPORT] Seven patients had nonprogressive myopia of 5.00 or more diopters. Vitreoretinal degeneration was encountered in six patients with high myopia, and vitreous syneresis was present in all patients. --- Explanation: Ophthalmic study of 18 SEDC patients documenting high myopia and universal vitreous syneresis.

[PMID:31824186] [SUPPORT] Ocular complications such as myopia have been reported in 45% of patients but retinal detachment is less frequent (12%) than in type 1 Strickler syndrome. --- Explanation: Review providing frequency data for myopia in SEDC.


MONDO:0008471

[PMID:31824186] [SUPPORT] Ocular complications such as myopia have been reported in 45% of patients but retinal detachment is less frequent (12%) than in type 1 Strickler syndrome. --- Explanation: Review quantifying retinal detachment frequency in SEDC at 12%.

[PMID:6807266] [PARTIAL] Retinal detachment was not encountered, although reports in the nonophthalmic literature claim up to 50% retinal detachment rate and poor visual prognosis in these patients. --- Explanation: This ophthalmic series did not observe retinal detachment in 18 patients, suggesting the true rate may be lower than some early reports claimed.


MONDO:0008471

[PMID:10743764] [SUPPORT] Hearing loss has been reported to occur in 25 to 30% of affected patients. To date, all reports of associated hearing loss have indicated the presence of a sensorineural component. --- Explanation: Documents hearing loss prevalence in SEDC patients and notes that hearing loss typically has a sensorineural component.

[PMID:31824186] [SUPPORT] Adult patients suffer from sensorineural (25% to 30% of reported cases) or less frequently mixed hearing loss. --- Explanation: Review confirming the 25-30% frequency of sensorineural hearing loss in SEDC.


MONDO:0008471

[PMID:31824186] [SUPPORT] Frequently patients suffer from atlantoaxial instability due to odontoid hypoplasia that can cause cervical cord compression, especially when repairing during intubation or surgery. --- Explanation: Review emphasizing the clinical significance of odontoid hypoplasia and the risk of cervical cord compression.


MONDO:0008471

[PMID:31824186] [SUPPORT] Adult patients also show flat face for skeletal hypoplasia with prominent eyes and cleft palate, barrel-chest and pectus carinatum. --- Explanation: Review documenting pectus carinatum as a recognized feature of adult SEDC patients.


MONDO:0008471

[PMID:31824186] [SUPPORT] coxa vara, dislocated hips, talipes equinovarus, clubfeet and waddling gate are reported --- Explanation: Review documenting coxa vara among the lower limb abnormalities in SEDC.


MONDO:0008471

[PMID:31824186] [SUPPORT] This ultimately leads to wedge-shaped thoracic vertebrae and severe kyphoscoliosis with lumbar lordosis. --- Explanation: Review documenting progressive kyphoscoliosis as a consequence of platyspondyly in SEDC.


MONDO:0008471

[PMID:31824186] [SUPPORT] coxa vara, dislocated hips, talipes equinovarus, clubfeet and waddling gate are reported --- Explanation: Review listing talipes equinovarus among the SEDC features.


MONDO:0008471

[PMID:31824186] [SUPPORT] coxa vara, dislocated hips, talipes equinovarus, clubfeet and waddling gate are reported --- Explanation: Review listing waddling gait as a reported feature.


MONDO:0008471


MONDO:0008471

[PMID:31824186] [SUPPORT] ossification is absent in pubic bones and distal femoral epiphyses, absent or reduced in cervical and sacral vertebras --- Explanation: Review detailing the pattern of absent or delayed ossification in neonatal SEDC.


MONDO:0008471

[PMID:31824186] [SUPPORT] Infants with severe SEDC are often stillborn or premature and die shortly after birth because of hypoventilation. --- Explanation: Review documenting that severe SEDC can be lethal due to respiratory insufficiency.


MONDO:0008471

[PMID:26443184] [INDIRECT EVIDENCE] [SUPPORT] One-third of the mutations are dominant-negative mutations that affect the glycine residue in the G-X-Y repeats of the alpha 1 chain. These mutations disrupt the collagen triple helix and are common in achondrogenesis type II and hypochondrogenesis. --- Explanation: This comprehensive mutation update of over 700 patients documents that glycine substitutions in the Gly-X-Y repeats are the predominant dominant-negative mechanism in type II collagenopathies including SEDC.

[PMID:29439465] [INDIRECT EVIDENCE] [SUPPORT] Retention of misfolded R740C and R789C proteins triggered an ER stress response leading to apoptosis of the expressing cells. Arginine to cysteine mutations towards the C-terminus of the triple helix had a deleterious effect, whereas mutations towards the N-terminus of the triple helix (R75C and R134C) and R704C had less impact. --- Explanation: In vitro study demonstrating that C-terminal arginine-to-cysteine mutations in collagen II cause ER retention, ER stress, and apoptosis, with a position-dependent gradient of severity.

[PMID:31824186] [INDIRECT EVIDENCE] [SUPPORT] The most common mutation (over 70%, Table 1) is missense mutation, some of which lead to substitution of glycine residue in the Gly-X-Y repeat, presenting as dominant-negative effect --- Explanation: Review confirming that glycine substitution missense mutations are the most common COL2A1 mutation type and act via dominant-negative effect.

[PMID:38076483] [INDIRECT EVIDENCE] [SUPPORT] Functional studies on father's cutaneous fibroblasts, along with in silico protein modeling and in vitro chondrocytes differentiation, showed intracellular accumulation of collagen-II, its localization in external Golgi vesicles and nuclear morphological alterations. Extracellular matrix showed a disorganized fibronectin network. --- Explanation: Functional studies of a COL2A1 glycine substitution demonstrate intracellular collagen accumulation, abnormal Golgi trafficking, and disorganized extracellular fibronectin network, confirming the dominant- negative effect on collagen processing and ECM assembly.


MONDO:0008471

[PMID:24475193] [INDIRECT EVIDENCE] [SUPPORT] Misfolded procollagen was largely synthesized and retained in dilated endoplasmic reticulum and the endoplasmic reticulum stress (ERS)-unfolded protein response (UPR)-apoptosis cascade was activated. Apoptosis occurred prior to hypertrophy, prevented the formation of a hypertrophic zone, disrupted normal chondrogenic signaling pathways, and eventually caused chondrodysplasia. --- Explanation: This col2a1 p.Gly1170Ser mouse model directly demonstrates that ER stress-UPR-apoptosis is the chief mechanism of chondrodysplasia caused by COL2A1 mutations.

[PMID:31824186] [INDIRECT EVIDENCE] [SUPPORT] chondrocytes show greatly extended cisternae of rough endoplasmic reticulum with a retention of procollagen and other molecules (eg, fibronectin). This retention hence causes endoplasmic reticulum stress sufficient to reduce proliferation rate at the growth plates. --- Explanation: Review summarizing that transgenic mouse models show ER retention of procollagen leading to ER stress and reduced proliferation in growth plates.


MONDO:0008471

[PMID:22028304] [INDIRECT EVIDENCE] [SUPPORT] Histology revealed growth plate disorganization in 14-day-old Lpk/+ mice and embryonic cartilage from Lpk/+ and Lpk/Lpk mice had reduced safranin-O and type-II collagen staining in the extracellular matrix. --- Explanation: The Longpockets (Lpk) ENU mouse model with Col2a1 Ser1386Pro mutation shows growth plate disorganization and reduced collagen II in the ECM, directly demonstrating the mechanism of growth plate disruption.

[PMID:31824186] [INDIRECT EVIDENCE] [SUPPORT] Proliferative and hypertrophic zones of cartilage were shorter or indistinguishable and deposition of cartilage matrix is notably impaired, collagen fibrils were fewer and less elaborate. --- Explanation: Review of transgenic mouse models demonstrating the characteristic growth plate disorganization in COL2A1 mutants.


MONDO:0008471

[PMID:6807266] [INDIRECT EVIDENCE] [SUPPORT] Eighteen patients had ocular changes associated with spondyloepiphyseal dysplasia congenita, a rare cause of congenital dwarfism with normal mental development. Seven patients had nonprogressive myopia of 5.00 or more diopters. Vitreoretinal degeneration was encountered in six patients with high myopia, and vitreous syneresis was present in all patients. --- Explanation: This ophthalmic case series of 18 SEDC patients systematically documents the vitreoretinal abnormalities including universal vitreous syneresis, high myopia, and vitreoretinal degeneration.

[PMID:7550321] [INDIRECT EVIDENCE] [SUPPORT] Individuals affected with these disorders exhibit abnormalities of the growth plate, nucleus pulposus, and vitreous humor, which are tissues that contain type II collagen. --- Explanation: This study documents that vitreous humor abnormalities are a feature of COL2A1-related chondrodysplasias due to type II collagen being a major component of the vitreous.


MONDO:0008471

[PMID:22155431] [INDIRECT EVIDENCE] [SUPPORT] The sedc/+ mouse did, however, show significantly higher OARSI scores in knee (9, 12 and 18 months) and temporomandibular joints at all ages examined. Histological staining showed regions of proteoglycan degradation as early as 2 months in both temporomandibular and knee joints of the mutant. --- Explanation: The heterozygous sedc mouse develops premature OA despite normal skeletal morphology, demonstrating that abnormal collagen II directly predisposes to cartilage degeneration.

[PMID:31958497] [INDIRECT EVIDENCE] [SUPPORT] Col2a1+/d mice developed a moderate skeletal phenotype expressed by reduced cortical and trabecular parameters at 4 weeks. Importantly, no articular defects could be observed in the knee joints at 4 weeks, while osteoarthritis was only detectable in 12-week-old mice. --- Explanation: Col2a1 heterozygous mice show skeletal deterioration with osteopenia that precedes the onset of osteoarthritis, supporting a primary bone defect contributing to secondary OA.

[PMID:31958497] [INDIRECT EVIDENCE] [SUPPORT] We identified a dominant COL2A1 mutation (c.620G > A p.(Gly207Glu)) indicating spondyloepiphyseal dysplasia in the female patient and her son, both being severely affected by skeletal deterioration. --- Explanation: Clinical data from a mother-son pair with COL2A1 mutation showing severe skeletal deterioration, with trabecular osteopenia in the child progressing over time.


MAXO:0000004

[PMID:31824186] [SUPPORT] Frequently patients suffer from atlantoaxial instability due to odontoid hypoplasia that can cause cervical cord compression, especially when repairing during intubation or surgery. --- Explanation: Review documenting the clinical significance of cervical instability in SEDC and the need for vigilance during surgical procedures and intubation.


MAXO:0000004

[PMID:31824186] [SUPPORT] coxa vara, dislocated hips, talipes equinovarus, clubfeet and waddling gate are reported --- Explanation: Review documenting the lower limb deformities in SEDC that require orthopedic management including hip dysplasia and foot deformities.

[PMID:31824186] [SUPPORT] This ultimately leads to wedge-shaped thoracic vertebrae and severe kyphoscoliosis with lumbar lordosis. --- Explanation: Review documenting progressive spinal deformity requiring orthopedic surveillance and possible surgical intervention.