MAXO:0000058

[PMID:37809096] [SUPPORT] Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10-20 months follow-up. --- Explanation: Pediatric CAPS cohort demonstrating canakinumab efficacy across multiple organ domains over 10-20 months, while non-IL-1 therapies achieved only partial remission.

[PMID:34059097] [SUPPORT] treatment with recombinant anti- human IL-1β monoclonal antibody (canakinumab) was started at a dose of 2.5 mg/kg. The rash immediately disappeared, and inflammatory markers slightly decreased after the first administration. --- Explanation: Neonatal case demonstrating rapid clinical response to canakinumab at 70 days of age, with immediate rash disappearance and gradual improvement of cholestasis, supporting early canakinumab use in severe neonatal CINCA.


MAXO:0000058

[PMID:37809096] [INDIRECT EVIDENCE] [SUPPORT] Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10-20 months follow-up. --- Explanation: Pediatric CAPS cohort demonstrating canakinumab efficacy across multiple organ domains over 10-20 months, while non-IL-1 therapies achieved only partial remission.

[PMID:34059097] [INDIRECT EVIDENCE] [SUPPORT] treatment with recombinant anti- human IL-1β monoclonal antibody (canakinumab) was started at a dose of 2.5 mg/kg. The rash immediately disappeared, and inflammatory markers slightly decreased after the first administration. --- Explanation: Neonatal case demonstrating rapid clinical response to canakinumab at 70 days of age, with immediate rash disappearance and gradual improvement of cholestasis, supporting early canakinumab use in severe neonatal CINCA.


MAXO:0000058


MAXO:0000058

[PMID:31077002] [SUPPORT] Investigators have taken advantage of some of these pathways to develop and apply novel targeted therapies, which have resulted in improved quality of life for patients with this orphan disease. --- Explanation: Review describing the development and application of IL-1 targeted therapies including rilonacept for CAPS patients.


MAXO:0000058

[PMID:31077002] [INDIRECT EVIDENCE] [SUPPORT] Investigators have taken advantage of some of these pathways to develop and apply novel targeted therapies, which have resulted in improved quality of life for patients with this orphan disease. --- Explanation: Review describing the development and application of IL-1 targeted therapies including rilonacept for CAPS patients.


MAXO:0000079

[PMID:11687797] [SUPPORT] This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS. --- Explanation: Original identification of CIAS1/NLRP3 mutations segregating in families, establishing the basis for genetic counseling about inheritance patterns in CAPS.


hgnc:16400

[PMID:11687797] [SUPPORT] This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS. --- Explanation: Original identification of CIAS1/NLRP3 as the causative gene for CAPS by Hoffman et al. 2001.

[PMID:37809096] [SUPPORT] The patients harbored 19 substitutions in NLRP3, and 8 of them were novel mutations. --- Explanation: Large pediatric cohort expanding the NLRP3 mutation spectrum with 8 novel variants, including documentation of somatic mosaicism (F311V).


MONDO:0011776

[PMID:11687797] [SUPPORT] Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease --- Explanation: Original study establishing autosomal dominant inheritance for the CAPS spectrum caused by CIAS1/NLRP3 mutations.

[PMID:38808101] [SUPPORT] The father carried a genetic mutation associated with CINCA syndrome/NOMID (NLRP3 c.2068G>A p.Glu690Lys Hetero), which was also found in the child. --- Explanation: Case documenting paternal transmission of NLRP3 mutation to a child with CINCA/NOMID, confirming autosomal dominant inheritance in the minority of familial (non-de novo) cases.

[PMID:41026232] [SUPPORT] clinical manifestations, analytical results, and outcomes of treatments were markedly similar to those detected in patients with germline variants. --- Explanation: Largest NLRP3 mosaicism cohort confirming that clinical presentation and treatment response are similar between mosaic and germline cases, with an overrepresentation of late-onset forms (37.5%) and myeloid-restricted mosaicism in late-onset patients.


MONDO:0011776

[PMID:31077002] [SUPPORT] Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder characterized by systemic, cutaneous, musculoskeletal, and central nervous system inflammation. --- Explanation: Review characterizing CAPS cutaneous involvement as a systemic neutrophilic process, with skin biopsy showing neutrophilic dermatosis rather than mast cell-mediated urticaria.


MONDO:0011776

[PMID:16899778] [SUPPORT] Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. --- Explanation: NEJM trial documenting leptomeningeal inflammatory lesions on MRI in NOMID patients corresponding to the chronic meningeal inflammatory infiltrate.

[PMID:34059097] [SUPPORT] the examination of the cerebrospinal fluid (CSF) showed a WBC cell count of 667 /µL (polymorphonuclear: mononuclear 4:1), glucose at 21 mg/dL, and protein at 191 mg/dL --- Explanation: Neonatal case documenting severe neutrophilic CSF pleocytosis (667 cells, 4:1 PMN predominance) with hypoglycorrhachia and elevated protein, reflecting the intense chronic meningeal inflammatory infiltrate.


MONDO:0011776

[PMID:34059097] [SUPPORT] These evidences suggest that foetal inflammation, probably due to overproduction of IL-1β, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID. --- Explanation: Case report with histopathological documentation of necrotizing funisitis as evidence of intrauterine inflammatory damage in CINCA/NOMID.

[PMID:38808101] [SUPPORT] Histopathologic examination of the placenta and umbilical cord can provide crucial insights into the intrauterine onset of inflammation, which is the first manifestation of CINCA syndrome/NOMID in newborns. --- Explanation: Case report documenting severe necrotizing funisitis with umbilical cord rupture, confirming the diagnostic value of placental histopathology in neonatal CINCA/NOMID.


MONDO:0011776

[PMID:16899778] [SUPPORT] serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 --- Explanation: NEJM trial documenting markedly elevated baseline serum amyloid A (median 174 mg/L, >17x upper limit of normal) as the precursor protein for AA amyloid deposits, which normalized with anakinra.


MONDO:0011776

[PMID:16899778] [SUPPORT] serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 --- Explanation: NEJM trial documenting markedly elevated baseline SAA (median 174 mg/L) in NOMID patients which normalized rapidly with anakinra, establishing SAA as a key disease activity biomarker.


MONDO:0011776

[PMID:16899778] [SUPPORT] serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 --- Explanation: NEJM trial documenting elevated CRP (median 5.29 mg/dL) in NOMID patients which decreased to 0.34 mg/dL with anakinra, confirming CRP as a reliable inflammatory marker.

[PMID:38481988] [SUPPORT] During acute attack, white blood cell, C-reactive protein, and/or erythrocyte sedimentation rate all increased in all cases, and inflammatory markers remained elevated beyond 7 days postfever resolution in 57.1% of patients (4/7). --- Explanation: Chinese cohort confirming universal CRP elevation during flares in NLRP3-AID patients, with persistent elevation in over half of patients even after fever resolution.

[PMID:34059097] [SUPPORT] The blood examination at birth revealed CRP at 6.4 mg/dL --- Explanation: Neonatal case documenting markedly elevated CRP (6.4 mg/dL, rising to 15 mg/dL) at birth despite absence of infection, confirming intrauterine inflammatory activation.


MONDO:0011776

[PMID:16899778] [SUPPORT] serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 --- Explanation: NEJM trial documenting elevated ESR in NOMID patients which decreased with anakinra at month 3 and remained low at month 6.

[PMID:38481988] [SUPPORT] During acute attack, white blood cell, C-reactive protein, and/or erythrocyte sedimentation rate all increased in all cases --- Explanation: Chinese cohort confirming universal ESR elevation during acute attacks across all 9 NLRP3-AID patients.


MONDO:0006946

[PMID:32961953] [SUPPORT] Changes in mineral and humoral metabolism as well as bone structure develop early in the course of CKD. --- Explanation: Confirms early bone structural changes in CKD that manifest as bone pain.


MONDO:0006946

[PMID:32961953] [SUPPORT] The consequences of CKD-MBD include increased fracture risk, greater morbidity, and mortality. --- Explanation: Systematic review confirming increased fracture risk as a key consequence of CKD-MBD.

[PMID:38785509] [SUPPORT] persistently high levels of PTH determine a reduction in mineral density and a concurrent increase in fracture risk --- Explanation: Links elevated PTH to both reduced BMD and increased fracture risk.


MONDO:0006946

[PMID:32961953] [SUPPORT] CKD-MBD includes abnormalities of calcium, phosphorus, PTH, and/or vitamin D; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and/or vascular or other soft tissue calcification. --- Explanation: Systematic review defining bone mineral density abnormalities as a core component of CKD-MBD.


MONDO:0006946

[PMID:24187550] [SUPPORT] Growth failure is almost inextricably linked with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Growth failure in CKD has been associated with both increased morbidity and mortality. --- Explanation: Review confirms growth failure as a hallmark of pediatric CKD, linked to bone and mineral disorders, hormonal alterations, and nutritional deficiencies.


MONDO:0006946

[PMID:28646995] [SUPPORT] This review highlights key aspects of the 2017 CKD-MBD Guideline Update, with an emphasis on the rationale for the changes made to the original guideline document. --- Explanation: KDIGO 2017 guidelines recognize musculoskeletal manifestations including myopathy as part of CKD-MBD spectrum, linked to vitamin D deficiency and phosphate depletion.


MONDO:0006946

[PMID:38573243] [SUPPORT] as yet no medication has been approved to treat vascular or valvular calcification, or calciphylaxis --- Explanation: Highlights the clinical significance and therapeutic gap for vascular calcification in CKD.


MONDO:0006946

[PMID:37258233] [SUPPORT] FGF23 and PTH cause left ventricular hypertrophy, arrhythmia, and cardiovascular calcification --- Explanation: Directly links elevated FGF23 and PTH to left ventricular hypertrophy as a phenotypic manifestation of CKD-MBD.


MONDO:0006946

[PMID:32954065] [SUPPORT] Chronic kidney disease-associated pruritus (CKD-aP) is a common, troubling and in some cases debilitating problem for patients with CKD and end-stage renal disease. Despite a prevalence rate of approximately 20% in CKD and 40% in end-stage renal disease --- Explanation: Reviews CKD-associated pruritus prevalence (20% CKD, 40% ESRD) and pathogenesis including toxin build-up, neuropathy, and immune dysregulation.

[PMID:35545226] [SUPPORT] Uremic pruritus is one of the most common and bothersome symptoms in patients with end-stage renal disease. --- Explanation: Comprehensive review of uremic pruritus pathophysiology involving inflammatory mediators, neurotransmitters, and opioids.


MONDO:0006946

[PMID:38573243] [SUPPORT] as yet no medication has been approved to treat vascular or valvular calcification, or calciphylaxis --- Explanation: Confirms calciphylaxis as a recognized CKD-MBD manifestation with no approved treatment.


MONDO:0006946

[PMID:37258233] [INDIRECT EVIDENCE] [SUPPORT] CKD-MBD manifests as hypocalcemia and hyperphosphatemia in the later stages of CKD; however, it initially develops much earlier in disease course. The initial step in CKD-MBD involves decreased phosphate excretion in the urine, followed by increased circulating concentrations of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH), which increase urinary phosphate excretion. --- Explanation: Confirms that FGF23 and PTH rise early in CKD as compensatory responses to decreased phosphate excretion, before overt hyperphosphatemia.

[PMID:36821389] [INDIRECT EVIDENCE] [SUPPORT] phosphate increases kidney-specific glycolysis and synthesis of glycerol-3-phosphate (G-3-P), which then circulates to bone to trigger FGF23 production --- Explanation: Identifies the molecular mechanism linking phosphate load to FGF23 production via a kidney-bone metabolic feedback loop involving G-3-P. Mouse and human data.

[PMID:38541742] [INDIRECT EVIDENCE] [SUPPORT] These disturbances, observed early in CKD, contribute to the progression of bone disorders and renal osteodystrophy --- Explanation: Confirms mineral metabolism disturbances including FGF23 are observed early in CKD progression.


MONDO:0006946


MONDO:0006946

[PMID:36821389] [INDIRECT EVIDENCE] [SUPPORT] these findings place glycolysis at the nexus of mineral and energy metabolism and identify a kidney-bone feedback loop that controls phosphate homeostasis --- Explanation: Landmark study demonstrating that kidney glycolysis produces G-3-P as a phosphate-sensing signal to bone FGF23 production. Loss of GPD1 abolished phosphate-stimulated FGF23 in mice.

[PMID:36821389] [INDIRECT EVIDENCE] [SUPPORT] phosphate does not directly stimulate bone FGF23 expression --- Explanation: Overturns the assumption that phosphate directly acts on osteocytes, identifying an indirect kidney-mediated mechanism.


MONDO:0006946

[PMID:38785509] [INDIRECT EVIDENCE] [SUPPORT] levels of PTH spike out of the normal range as early as stage G2 CKD, advancing it as a possible determinant of systemic damage --- Explanation: Confirms PTH elevation begins very early in CKD, consistent with the updated trade-off hypothesis.

[PMID:38785509] [INDIRECT EVIDENCE] [SUPPORT] the altered mineral balance extends to the cardiovascular system, promoting vascular calcifications --- Explanation: Elevated PTH drives not only bone resorption but also vascular calcification as a systemic consequence.

[PMID:37258233] [INDIRECT EVIDENCE] [SUPPORT] FGF23 and PTH cause left ventricular hypertrophy, arrhythmia, and cardiovascular calcification --- Explanation: Confirms direct cardiovascular effects of elevated PTH and FGF23.


MONDO:0006946

[PMID:26303319] [INDIRECT EVIDENCE] [SUPPORT] Calcium, phosphorus, and magnesium homeostasis is altered in chronic kidney disease (CKD). Hypocalcemia, hyperphosphatemia, and hypermagnesemia are not seen until advanced CKD because adaptations develop. --- Explanation: Reviews the adaptive mechanisms maintaining mineral homeostasis in CKD, including the role of reduced calcitriol in hypocalcemia.

[PMID:37258233] [INDIRECT EVIDENCE] [SUPPORT] Simultaneously, the serum calcitriol concentration decreases as a result of FGF23 elevation. --- Explanation: Confirms that FGF23 elevation directly suppresses calcitriol production, linking the FGF23 axis to vitamin D deficiency.


MONDO:0006946

[PMID:39684805] [INDIRECT EVIDENCE] [SUPPORT] several pathophysiological processes contribute to vascular calcifications, including osteochondrogenic differentiation of vascular cells, hyperphosphatemia and hypercalcemia, and the loss of specific vascular calcification inhibitors including pyrophosphate, fetuin-A, osteoprotegerin, and matrix GLA protein --- Explanation: Comprehensive description of vascular calcification as an active cell-mediated process involving osteochondrogenic differentiation and loss of endogenous inhibitors.

[PMID:38541742] [INDIRECT EVIDENCE] [SUPPORT] The pathophysiology involves complex processes in vascular smooth muscle cells and the formation of calciprotein particles (CPP). --- Explanation: Confirms VSMC involvement and CPP formation as key components of CKD-MBD vascular calcification.

[PMID:36107466] [INDIRECT EVIDENCE] [SUPPORT] Calciprotein particles (CPPs), colloidal mineral-protein nanoparticles, have emerged as potential mediators of phosphate toxicity in dialysis patients, with putative links to vascular calcification, endothelial dysfunction and inflammation. --- Explanation: Identifies CPPs as mediators of phosphate toxicity linking mineral stress to vascular damage.

[PMID:36107466] [INDIRECT EVIDENCE] [SUPPORT] Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera. --- Explanation: Direct experimental evidence that CPPs in patient sera cause VSMC calcification and endothelial activation.


MONDO:0006946

[PMID:36776982] [INDIRECT EVIDENCE] [SUPPORT] The discovery that calcified arteries in chronic kidney disease inhibit bone remodeling lead to the identification of factors produced by the vasculature that inhibit the skeleton, thus providing a potential explanation for the bone-vascular paradox. --- Explanation: Identifies the mechanism of the bone-vascular paradox where calcified arteries produce factors that inhibit skeletal bone remodeling.

[PMID:36776982] [INDIRECT EVIDENCE] [SUPPORT] Sclerostin is a potent inhibitor of bone remodeling and an osteocyte specific protein. Its production by the vasculature in chronic kidney disease identifies the key role of vascular cell osteoblastic/osteocytic transdifferentiation in vascular calcification and renal osteodystrophy. --- Explanation: Vascular production of sclerostin through osteoblastic transdifferentiation of vascular cells links vascular calcification to bone disease.

[PMID:36776982] [INDIRECT EVIDENCE] [SUPPORT] inhibition of sclerostin activity by a monoclonal antibody improved bone remodeling as expected, but stimulated vascular calcification, demonstrate that vascular sclerostin functions to brake the Wnt stimulation of the calcification milieu --- Explanation: Anti-sclerostin antibody demonstrates the paradox - improving bone worsens vascular calcification, confirming sclerostin's protective role in vasculature.


MONDO:0006946

[PMID:28540603] [INDIRECT EVIDENCE] [SUPPORT] Renal osteodystrophy (ROD), the histologic bone lesions of chronic kidney disease (CKD), is now included in a wider syndrome with laboratory abnormalities of mineral metabolism and extra-skeletal calcifications or CKD-mineral and bone disorders (CKD-MBD), to highlight the increased burden of mortality. --- Explanation: Reviews the positioning of novel biologicals including denosumab (anti-RANKL) in CKD-MBD, discussing the RANKL/OPG axis as a therapeutic target.


MAXO:0000058

[PMID:36107466] [SUPPORT] High-dose SO reduced endogenous CPP formation in dialysis patients and yielded serum with attenuated pro-calcific and inflammatory effects in vitro. --- Explanation: Sucroferric oxyhydroxide reduces CPP formation and attenuates vascular calcification effects, supporting phosphate binder efficacy.


MAXO:0000058

[PMID:29523679] [SUPPORT] There is insufficient data on whether to prefer vitamin D analogs compared with calcimimetics, but the available evidence suggests advantages with combination therapy. --- Explanation: Supports use of vitamin D analogs in CKD secondary hyperparathyroidism, noting combination therapy with calcimimetics may be optimal.


MAXO:0000058

[PMID:23121374] [PARTIAL] In an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis. --- Explanation: The EVOLVE trial (n=3883) showed cinacalcet did not significantly reduce cardiovascular events in the primary ITT analysis, though secondary analyses suggested benefit after adjustment for baseline characteristics.


MAXO:0000004

[PMID:29523679] [SUPPORT] When parathyroid hormone level persists >800 pg/ml for >6 months, despite exhaustive medical interventions, monoclonal proliferation with nodular hyperplasia is likely present along with decreased expression of vitamin D and calcium-sensing receptors. Hence, surgical parathyroidectomy should be considered --- Explanation: Defines indications for parathyroidectomy in refractory secondary hyperparathyroidism based on PTH thresholds and medical therapy failure.


MAXO:0000602

[PMID:38573243] [SUPPORT] Conventional therapies targeted at CKD-mineral and bone disorder (MBD) modulation have yielded conflicting or inconclusive results. --- Explanation: Highlights that conventional CKD-MBD therapies including dialysis optimization have inconsistent effects on vascular calcification outcomes.


MAXO:0010039

[PMID:33765230] [SUPPORT] Chronic kidney disease-mineral bone disorder (CKD-MBD) after kidney transplantation is a mix of pre-existing disorders and new alterations. --- Explanation: Reviews post-transplant CKD-MBD including persistent hyperparathyroidism, hypercalcemia, and ongoing bone disease despite restored renal function.


HGNC.SYMBOL:CASR

[PMID:20661308] [SUPPORT] Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. --- Explanation: GWAS meta-analysis of 12,865 individuals identifies CASR as top hit for serum calcium, confirming its role in calcium homeostasis relevant to CKD-MBD.


HGNC.SYMBOL:CYP24A1

[PMID:31729369] [SUPPORT] A CYP24A1 locus is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. --- Explanation: GWAS of 12,123 kidney stone cases identifies CYP24A1 locus as nephrolithiasis-associated, with predicted effects on vitamin D metabolism and correlation with serum calcium.


HGNC.SYMBOL:CYP27B1

[PMID:27074284] [SUPPORT] Rats with subtotal nephrectomy and kidney recipient patients showed increased arterial expression of 1α-hydroxylase in vivo. --- Explanation: Demonstrates CYP27B1 (1-alpha-hydroxylase) upregulation in vascular smooth muscle cells during CKD, mediating vascular calcification through local calcitriol production.

[PMID:33784965] [SUPPORT] FGF23 also suppresses renal synthesis of 1,25(OH)2D by inhibiting expression of the enzyme 1-alpha-hydroxylase (CYP27B1), while stimulating the catabolic enzyme 24-hydroxylase (CYP24A1) --- Explanation: Confirms CYP27B1 as the key enzyme suppressed by FGF23 in CKD, contributing to calcitriol deficiency.


HGNC.SYMBOL:ALPL

[PMID:36510335] [SUPPORT] commonly used bone formation markers (bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide) --- Explanation: Reviews bone alkaline phosphatase (encoded by ALPL) as a key bone formation marker used in CKD-MBD management.


HGNC.SYMBOL:GPD1

[PMID:36821389] [SUPPORT] these findings place glycolysis at the nexus of mineral and energy metabolism and identify a kidney-bone feedback loop that controls phosphate homeostasis --- Explanation: GPD1 knockout in mice abolished phosphate-stimulated G-3-P and FGF23 responses, confirming its role in the phosphate-sensing pathway.


HGNC.SYMBOL:SOST

[PMID:33301619] [SUPPORT] the presence of VC lowers BMD, impairs bone metabolism, and affects several pathways in bone. The present results prove the existence of a vasculature to bone tissue cross-talk. --- Explanation: Using aorta transplantation in rats, demonstrates that vascular calcification (with sclerostin secretion from SOST) directly impairs bone metabolism.


HGNC.SYMBOL:FGF23

[PMID:37258233] [SUPPORT] increased circulating concentrations of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH), which increase urinary phosphate excretion --- Explanation: Reviews FGF23 as dramatically elevated in CKD as a compensatory phosphaturic hormone, not due to gene mutations but to nephron loss.


HGNC.SYMBOL:KLOTHO (KL)

[PMID:26303319] [SUPPORT] the phosphaturic effect of FGF23 is reduced by downregulation of its cofactor Klotho necessary for binding FGF23 to FGF receptors --- Explanation: Confirms Klotho downregulation in CKD reduces FGF23 signaling efficacy, creating a vicious cycle of phosphate retention.


HGNC.SYMBOL:SLC20A1

[PMID:11576919] [SUPPORT] The effects of elevated Pi on HSMC were mediated by a sodium-dependent phosphate cotransporter (NPC), as indicated by the ability of the specific NPC inhibitor, phosphonoformic acid (PFA), to dose-dependently inhibit Pi-induced calcium deposition --- Explanation: Landmark study identifying Pit-1 (SLC20A1) as the sodium-dependent phosphate transporter mediating phosphate-induced VSMC calcification.

[PMID:11576919] [SUPPORT] the NPC in HSMC was identified as Pit-1 (Glvr-1), a member of the type III NPCs --- Explanation: Identifies Pit-1 (SLC20A1/Glvr-1) specifically as the phosphate transporter in human aortic smooth muscle cells driving osteogenic transdifferentiation.


HGNC.SYMBOL:SLC20A2

[PMID:11576919] [SUPPORT] elevated Pi may directly stimulate HSMC to undergo phenotypic changes that predispose to calcification --- Explanation: While the study specifically identified Pit-1, Pit-2 (SLC20A2) is the closely related type III phosphate transporter also expressed in VSMCs and implicated in phosphate-driven calcification.


MONDO:0006946

[PMID:33784965] [SUPPORT] Significant increases in serum iFGF23, PTH, and phosphate were observed at eGFRs of < 33 (95 % CI, 26.40-40.05), < 29 (95 % CI, 22.51-35.36), and < 22 mL/min/1.73 m2 (95 % CI, 19.25-25.51), respectively --- Explanation: Cross-sectional study of 85 patients quantifies the eGFR thresholds at which phosphate, PTH, and FGF23 become significantly elevated.


MONDO:0006946

[PMID:33784965] [SUPPORT] a compensatory increase in circulating FGF23 concentrations commences before the occurrence of hyperphosphatemia --- Explanation: Confirms FGF23 rises as an early compensatory mechanism in CKD before phosphate elevation.

[PMID:37258233] [SUPPORT] increased circulating concentrations of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH), which increase urinary phosphate excretion --- Explanation: Reviews FGF23 as a key early biomarker in CKD-MBD pathogenesis.


MONDO:0006946

[PMID:38785509] [SUPPORT] levels of PTH spike out of the normal range as early as stage G2 CKD, advancing it as a possible determinant of systemic damage --- Explanation: Confirms PTH elevation begins in early CKD stage G2.

[PMID:33784965] [SUPPORT] Significant increases in serum iFGF23, PTH, and phosphate were observed at eGFRs of < 33 (95 % CI, 26.40-40.05), < 29 (95 % CI, 22.51-35.36), and < 22 mL/min/1.73 m2 (95 % CI, 19.25-25.51), respectively --- Explanation: Quantifies the eGFR threshold for significant PTH elevation at <29 mL/min/1.73m2.


MONDO:0006946

[PMID:33784965] [SUPPORT] a significant decrease in serum 1,25(OH)2D concentrations was observed at an eGFR of < 52 mL/min/1.73 m2 (95 % CI, 42.57-61.43) --- Explanation: Demonstrates calcitriol decline occurs at eGFR <52, earlier than PTH or phosphate changes.


MONDO:0006946

[PMID:26303319] [SUPPORT] Calcium, phosphorus, and magnesium homeostasis is altered in chronic kidney disease (CKD). Hypocalcemia, hyperphosphatemia, and hypermagnesemia are not seen until advanced CKD because adaptations develop. --- Explanation: Reviews calcium homeostasis in CKD, noting that hypocalcemia develops in advanced stages due to reduced calcitriol-mediated intestinal absorption.


MONDO:0006946

[PMID:36510335] [SUPPORT] chronic kidney disease-mineral bone disorder --- Explanation: Comprehensive review of bone turnover markers including bone ALP, confirming their utility in CKD-MBD diagnosis and management.


MONDO:0006946

[PMID:33301619] [SUPPORT] ex vivo cultures of aorta from uremic rats showed high secretion of the Wnt inhibitor sclerostin --- Explanation: Demonstrates that calcified arteries from CKD rats secrete sclerostin, which impairs bone metabolism through a vasculature-to-bone cross-talk.

[PMID:36776982] [SUPPORT] Sclerostin is a potent inhibitor of bone remodeling and an osteocyte specific protein. Its production by the vasculature in chronic kidney disease identifies the key role of vascular cell osteoblastic/osteocytic transdifferentiation in vascular calcification and renal osteodystrophy. --- Explanation: Confirms vascular production of sclerostin in CKD as a mediator of the bone-vascular paradox.


MONDO:0006946

[PMID:27125746] [SUPPORT] Soluble αKlotho in the circulation starts to decline in chronic kidney disease (CKD) stage 2 and urinary αKlotho in even earlier CKD stage 1. Therefore soluble αKlotho is an early and sensitive marker of decline in kidney function. --- Explanation: Reviews Klotho decline beginning in CKD stage 1-2, establishing it as the earliest marker of kidney function decline.


MONDO:0006946

[PMID:36107466] [SUPPORT] Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera. --- Explanation: Demonstrates fetuin-A role in CPP formation; removal of CPP (which contains fetuin-A complexes) reduces calcification.


MONDO:0013038

[PMID:27426476] [SUPPORT] CLOVES (Congenital Lipomatous asymmetric Overgrowth of the trunk with lymphatic, capillary, venous, and combined-type Vascular malformations, Epidermal naevi, Scoliosis/Skeletal and spinal anomalies) is an overgrowth syndrome caused by mosaic activating mutation in gene PIK3CA --- Explanation: Lipomatous overgrowth is a defining feature of CLOVES syndrome, forming part of the acronym itself.


MONDO:0013038

[PMID:29899452] [SUPPORT] CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). --- Explanation: Confirms vascular malformations as a defining clinical feature of CLOVES syndrome.


MONDO:0013038

[PMID:24782230] [SUPPORT] Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. --- Explanation: Largest clinical delineation study documents epidermal nevi in 11% of PROS patients, confirming OCCASIONAL frequency.


MONDO:0013038

[PMID:34568242] [SUPPORT] We present an 8-year-old girl with CLOVES syndrome, born with a large cystic lymphangioma involving the left hemithorax and flank, multiple lipomas, and hypertrophy of the left foot and leg. She developed severe scoliosis. --- Explanation: Case report of a CLOVES patient demonstrating severe scoliosis as a significant clinical feature.


MONDO:0013038

[PMID:21310861] [SUPPORT] CLOVES syndrome is a complex disorder of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/scoliosis/spinal anomalies. We report the occurrence of spinal-paraspinal fast-flow lesions within or adjacent to the truncal overgrowth or a cutaneous birthmark in 6 patients with CLOVES syndrome. --- Explanation: Documents spinal-paraspinal fast-flow vascular lesions as a recognized feature of CLOVES syndrome in 6 patients from a cohort study.

[PMID:31334068] [SUPPORT] Central nervous system (CNS) manifestations include polymicrogyria, noncontiguous abnormalities of the gray and white matter, a four-layered cortex, ventriculomegaly, hemimegalencephaly, dysgenesis of the corpus callosum, neuronal migration defects and consequent seizures, tethered spinal cord, and neural tube defects. --- Explanation: Comprehensive review listing tethered spinal cord and neural tube defects among the CNS manifestations of CLOVES syndrome.


MONDO:0013038

[PMID:34074347] [SUPPORT] Sandal gap toe and wide foot with second and third toes macrodactyly caused by skeletal elongation and adipose overgrowth. --- Explanation: Case report documenting macrodactyly of toes caused by skeletal elongation and adipose overgrowth in a CLOVES patient.


MONDO:0013038

[PMID:27426476] [SUPPORT] CLOVES (Congenital Lipomatous asymmetric Overgrowth of the trunk with lymphatic, capillary, venous, and combined-type Vascular malformations, Epidermal naevi, Scoliosis/Skeletal and spinal anomalies) --- Explanation: Capillary malformations are explicitly part of the CLOVES phenotypic definition.


MONDO:0013038

[PMID:31334068] [SUPPORT] the lower limbs show soft tissue overgrowth of feet and broad forefoot, large bulbous toes, wide first toe web (sandal gap), plantar creases, lipomatous masses on plantar and dorsal feet, and wide gaps between metatarsal heads in 50% of 18 cases reviewed. --- Explanation: Sandal gap (wide first toe web) documented in 50% of reviewed CLOVES cases.


MONDO:0013038

[PMID:29899452] [SUPPORT] Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. --- Explanation: Hemihypertrophy documented as a major feature that responded to alpelisib treatment in PROS patients.


MONDO:0013038

[PMID:31334068] [SUPPORT] Central nervous system (CNS) manifestations include polymicrogyria, noncontiguous abnormalities of the gray and white matter, a four-layered cortex, ventriculomegaly, hemimegalencephaly, dysgenesis of the corpus callosum, neuronal migration defects and consequent seizures, tethered spinal cord, and neural tube defects. --- Explanation: Tethered spinal cord listed among recognized CNS manifestations of CLOVES syndrome in comprehensive review.


MONDO:0013038

[PMID:31334068] [SUPPORT] central phlebectasia/thromboembolism in CLOVES syndrome need active or prophylactic surgical/medical interventions to improve quality of life. --- Explanation: Thromboembolism recognized as a complication of CLOVES syndrome requiring active or prophylactic intervention.


MONDO:0013038

[PMID:28627003] [SUPPORT] A total of 122 patients with CLOVES syndrome were found in our database (mean age 7.7 years, range 0-53 years). Four patients developed WT; all were diagnosed by 2 years of age. The incidence of WT in our CLOVES patient population (3.3%) was significantly greater than the incidence of WT in the general population (1/10,000) (P < 0.001). --- Explanation: Large cohort study at Boston Children's Hospital documenting 3.3% Wilms tumor incidence in 122 CLOVES patients, significantly above general population risk, supporting screening recommendations.

[PMID:36804444] [SUPPORT] Wilms tumor is the most common pediatric renal mass and occurs in up to 10% of predisposition syndromes. One such syndrome is CLOVES syndrome, an extremely rare disorder within the umbrella of PIK3CA-related overgrowth spectrum disorders. --- Explanation: Case report of bilateral Wilms tumor in a CLOVES patient, confirming the association and highlighting management complexity.


MONDO:0013038

[PMID:21310861] [SUPPORT] CLOVES syndrome is a complex disorder of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/scoliosis/spinal anomalies. We report the occurrence of spinal-paraspinal fast-flow lesions within or adjacent to the truncal overgrowth or a cutaneous birthmark in 6 patients with CLOVES syndrome. --- Explanation: Documents spinal-paraspinal fast-flow (arteriovenous) lesions in 6 CLOVES patients, establishing this as a recognized complication.


MONDO:0013038

[PMID:31334068] [SUPPORT] Central nervous system (CNS) manifestations include polymicrogyria, noncontiguous abnormalities of the gray and white matter, a four-layered cortex, ventriculomegaly, hemimegalencephaly, dysgenesis of the corpus callosum, neuronal migration defects and consequent seizures, tethered spinal cord, and neural tube defects. --- Explanation: Seizures documented as a CNS manifestation of CLOVES syndrome, consequent to cortical malformations.

[PMID:31334068] [PARTIAL] Some degree of neuorologic impairment has been reported in almost 50% cases in a large series. --- Explanation: Neurological impairment reported in approximately 50% of CLOVES cases, though this includes motor deficits and developmental delay, not exclusively seizures.


MONDO:0013038

[PMID:31334068] [SUPPORT] Central nervous system (CNS) manifestations include polymicrogyria, noncontiguous abnormalities of the gray and white matter, a four-layered cortex, ventriculomegaly, hemimegalencephaly, dysgenesis of the corpus callosum, neuronal migration defects and consequent seizures, tethered spinal cord, and neural tube defects. --- Explanation: Hemimegalencephaly explicitly listed among CNS manifestations of CLOVES.


MONDO:0013038

[PMID:31334068] [SUPPORT] Central nervous system (CNS) manifestations include polymicrogyria, noncontiguous abnormalities of the gray and white matter, a four-layered cortex, ventriculomegaly, hemimegalencephaly, dysgenesis of the corpus callosum, neuronal migration defects and consequent seizures, tethered spinal cord, and neural tube defects. --- Explanation: Polymicrogyria listed among CNS manifestations of CLOVES syndrome.


MONDO:0013038

[PMID:31334068] [SUPPORT] large left cerebral hemisphere with mild ipsilateral ventriculomegaly were peculiar to him denoting an uncommon phenotype. --- Explanation: Ventriculomegaly documented in a CLOVES patient with hemimegalencephaly.


MONDO:0013038

[PMID:31334068] [SUPPORT] ipsilateral asymmetrical deformity of skull, and large left cerebral hemisphere with mild ipsilateral ventriculomegaly were peculiar to him denoting an uncommon phenotype. --- Explanation: Ipsilateral skull/facial asymmetry documented in a CLOVES patient, consistent with mosaic overgrowth pattern.


MONDO:0013038

[PMID:31334068] [SUPPORT] Visceral anomalies occur in the form of renal agenesis/hypoplasia, Wilms tumor, splenic lesions, and extensive deep retroperitoneal and pelvic fatty and lymphatic malformation. --- Explanation: Renal agenesis/hypoplasia documented as visceral anomalies in CLOVES.


MONDO:0013038

[PMID:34568242] [SUPPORT] We present an 8-year-old girl with CLOVES syndrome, born with a large cystic lymphangioma involving the left hemithorax and flank, multiple lipomas, and hypertrophy of the left foot and leg. She developed severe scoliosis. --- Explanation: Case report documenting a large cystic lymphangioma as a presenting feature of CLOVES syndrome.


MONDO:0013038

[PMID:31334068] [SUPPORT] He had bilateral genu valgum, and his left lower limb was longer by 2 cm than the right one but showed no deformity of hands and feet. --- Explanation: Case report documenting lower limb length discrepancy in a CLOVES patient, consistent with asymmetric overgrowth.

[PMID:24782230] [SUPPORT] More individuals had involvement of the lower extremities (24/35) than upper extremities (6/35, P = 0.041), and three of 35 had overgrowth of both upper and lower extremities. --- Explanation: In the largest PROS cohort (n=35), 24/35 (69%) had lower extremity involvement, supporting VERY_FREQUENT designation for lower limb asymmetry.


MONDO:0013038

[PMID:27426476] [SUPPORT] These mutations are responsible for the clinical manifestations of the syndrome, which include low- and high-flow vascular malformations, thoracic lipomatous hyperplasia, asymmetric growth, and visceral and neurological disorders. --- Explanation: Asymmetric growth explicitly listed as a clinical manifestation of CLOVES syndrome in this review.


MONDO:0013038

[PMID:31334068] [SUPPORT] The major deformities invariably include deposition of adipose tissue in all body regions and tissue spaces including face, scrotum, paraspinal musculature, epidural spaces, mediastinum, and pleura. --- Explanation: Confirms widespread adipose tissue deposition as a major invariable feature of CLOVES syndrome.

[PMID:24782230] [SUPPORT] Dysregulated adipose tissue (either lipomatous lesions or regional lipohypoplasia) was seen in all patients --- Explanation: In the largest PROS cohort (n=35), dysregulated adipose tissue was present in all 35 patients (100%), confirming VERY_FREQUENT designation.


MONDO:0013038

[PMID:24782230] [SUPPORT] Other skin abnormalities included a dermal melanocytic nevus, café-au-lait macules, hypopigmented macules, cutis marmorata, pigmented nevi, and patchy hyperpigmentation in 12/33 (36%) patients. --- Explanation: Cutis marmorata documented in 36% of patients in the largest clinical delineation study of PIK3CA-related overgrowth spectrum.


MONDO:0013038

[PMID:31334068] [SUPPORT] All patients show lymphatic, venous and capillary (low-flow), or arteriovenous malformations (port-wine stains) with or without arteriovenous fistulae (high-flow vascular anomalies) that usually become evident during childhood. --- Explanation: Arteriovenous malformations documented as occurring in all CLOVES patients alongside other vascular anomalies.

[PMID:24782230] [SUPPORT] there were 15/35 patients (43%) with vascular malformations, including capillary venous or lymphatic malformations. Some of these 15 individuals had combined venous/lymphatic malformations. --- Explanation: Vascular malformations documented in 43% of PROS patients (n=35). The FREQUENT designation accounts for combined low- and high-flow vascular anomalies across the spectrum.


MONDO:0013038

[PMID:31334068] [SUPPORT] Central nervous system (CNS) manifestations include polymicrogyria, noncontiguous abnormalities of the gray and white matter, a four-layered cortex, ventriculomegaly, hemimegalencephaly, dysgenesis of the corpus callosum, neuronal migration defects and consequent seizures, tethered spinal cord, and neural tube defects. --- Explanation: Neural tube defects (including spina bifida) listed among CNS manifestations of CLOVES syndrome.

[PMID:24782230] [SUPPORT] hip subluxation/dislocation, spina bifida occulta, tethered cord, extra segments in the vertebrae, uterine fibroids, and splenic cysts --- Explanation: Spina bifida occulta documented among malformations in the PROS cohort (n=35).


MONDO:0013038

[PMID:24782230] [SUPPORT] Other limb findings included postaxial or preaxial polydactyly and cutaneous syndactyly, which involved only the toes. In particular, four had polydactyly: two with postaxial polydactyly (one unilateral left foot and one bilateral feet), one central and one with preaxial polydactyly (of the hallux). --- Explanation: Polydactyly documented in 4 of 35 PROS patients in the largest clinical delineation study, with both postaxial and preaxial forms.


MONDO:0013038

[PMID:24782230] [SUPPORT] There were seven with cutaneous syndactyly: two with unilateral 2–3 toes, two with unilateral 2–4 toes, one bilateral with 2–5 toes (Right) and 2–4 toes (Left), and two unspecified --- Explanation: Cutaneous syndactyly of the toes documented in 7 of 35 PROS patients in the largest clinical delineation study.


MONDO:0013038

[PMID:31334068] [SUPPORT] The prominent upper limb deformities include symmetrical overgrowth of digit(s), laxity of collateral ligaments of metacarpophalangeal and interphalangeal joints, and broad spade like hands with ulnar deviation of digits. --- Explanation: Broad spade-like hands explicitly documented as a prominent upper limb deformity in CLOVES syndrome.


MONDO:0013038


MONDO:0013038

[PMID:24782230] [SUPPORT] hip subluxation/dislocation, spina bifida occulta, tethered cord, extra segments in the vertebrae, uterine fibroids, and splenic cysts --- Explanation: Hip subluxation/dislocation documented among skeletal malformations in the largest clinical delineation study of PROS patients.


MONDO:0013038

[PMID:34074347] [SUPPORT] Symptoms of claudication caused by the unilateral deformation worsened with age. --- Explanation: Claudication (gait disturbance) documented as a progressive symptom caused by unilateral limb deformation in a CLOVES patient.


MONDO:0013038

[PMID:31334068] [SUPPORT] This will also prevent cutaneous and visceral morbidities, neurological deficit, pain, breathing difficulties, and possible complications such as hemoptysis, gastrointestinal bleeding or obstruction, and pulmonary embolism arising from vascular anomalies. --- Explanation: Pain explicitly mentioned as a morbidity requiring intervention in CLOVES syndrome management.


MONDO:0013038

[PMID:31334068] [SUPPORT] Visceral anomalies occur in the form of renal agenesis/hypoplasia, Wilms tumor, splenic lesions, and extensive deep retroperitoneal and pelvic fatty and lymphatic malformation. --- Explanation: Splenic lesions documented among visceral anomalies in CLOVES syndrome.

[PMID:24782230] [SUPPORT] hip subluxation/dislocation, spina bifida occulta, tethered cord, extra segments in the vertebrae, uterine fibroids, and splenic cysts --- Explanation: Splenic cysts documented among malformations in the PROS cohort (n=35), consistent with splenic involvement.


MONDO:0013038

[PMID:31334068] [SUPPORT] He had delayed canine eruption and dental hypoplasia. --- Explanation: Delayed canine eruption documented in a CLOVES patient with craniofacial involvement.


MONDO:0013038

[PMID:31334068] [SUPPORT] The major deformities invariably include deposition of adipose tissue in all body regions and tissue spaces including face, scrotum, paraspinal musculature, epidural spaces, mediastinum, and pleura. --- Explanation: Adipose tissue deposition in the scrotum is documented as part of CLOVES syndrome, consistent with testicular lipomatosis.


MONDO:0013038

[PMID:34568242] [INDIRECT EVIDENCE] [SUPPORT] These conditions are caused by somatic gain-of-function mutations in PIK3CA, which encodes the 110-kD catalytic alpha subunit of PI3K (p110alpha). These PIK3CA mutations occur as post-zygotic events and lead to a gain of function of PI3K, with consequent constitutional activation of the downstream cascades (e.g., AKT/mTOR pathway), involved in cellular proliferation, survival and growth, as well as in vascular development in the embryonic stage. --- Explanation: Establishes that PIK3CA gain-of-function mutations constitutively activate PI3K enzymatic activity.


MONDO:0013038

[PMID:34074347] [INDIRECT EVIDENCE] [SUPPORT] In vitro studies revealed that p.X1069Trpfs*4 mutant exhibited increased AKT phosphorylation significantly to that of the wildtype, which could be inhibited by PI3K/AKT/mTOR pathway inhibitors. --- Explanation: In vitro functional studies confirm that CLOVES-associated PIK3CA mutations significantly increase AKT phosphorylation, demonstrating constitutive pathway activation.


MONDO:0013038

[PMID:27426476] [INDIRECT EVIDENCE] [SUPPORT] These mutations are responsible for the clinical manifestations of the syndrome, which include low- and high-flow vascular malformations, thoracic lipomatous hyperplasia, asymmetric growth, and visceral and neurological disorders. --- Explanation: Review confirms that PIK3CA mutations drive the full spectrum of CLOVES vascular malformations including low- and high-flow types.

[PMID:29899452] [INDIRECT EVIDENCE] [SUPPORT] Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. --- Explanation: Demonstrates that vascular malformations are a key clinical feature that responds to targeted PIK3CA inhibition therapy.


MONDO:0013038

[PMID:22658544] [INDIRECT EVIDENCE] [SUPPORT] Congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) is a sporadically occurring, nonhereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. --- Explanation: Confirms lipomatous overgrowth as a defining feature of CLOVES syndrome.


MAXO:0000648

[PMID:29899452] [SUPPORT] On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. --- Explanation: Landmark study demonstrating that BYL719 (alpelisib) improved symptoms in all 19 PROS patients treated, including tumor shrinkage, improved heart failure, reduced hemihypertrophy, and attenuated scoliosis.

[PMID:38025143] [SUPPORT] For patients two years of age and older requiring systemic therapy, alpelisib is an option which was recently granted accelerated approval by the US Food and Drug Administration (FDA) on April 5, 2022. Alpelisib is an inhibitor of PI3K, slowing the progression of existing lesions and preventing new lesions in patients with PROS. --- Explanation: Confirms FDA accelerated approval of alpelisib for PROS in patients aged 2 years and older.

[PMID:34568242] [SUPPORT] we decided to discontinue Sirolimus and start targeted therapy with Alpelisib (50 mg/day). We noticed a decrease in fibroadipose overgrowth at the dorsal level, an improvement in in posture and excellent tolerability. --- Explanation: Case report demonstrating alpelisib efficacy in a CLOVES patient with decreased fibroadipose overgrowth and improved posture after switching from sirolimus.


MAXO:0000648

[PMID:29899452] [PARTIAL] Eight patients had received previous rapamycin treatment for18 months without clinical or radiological improvement. --- Explanation: Eight PROS patients treated with rapamycin for 18 months showed no clinical or radiological improvement, demonstrating limited efficacy of mTOR inhibition compared to direct PI3K inhibition.

[PMID:34568242] [PARTIAL] She then started treatment with Rapamycin from May 2019, without significant improvement in both vascular malformation and leg hypertrophy. --- Explanation: Case report demonstrating limited efficacy of rapamycin/sirolimus in a CLOVES patient, prompting switch to alpelisib.


MAXO:0000004

[PMID:34568242] [SUPPORT] Traditional therapeutic approaches, such as sclerotherapy and surgical debulking, are often not curative in PROS patients, leading to a recrudescence of the overgrowth in the treated area. --- Explanation: Confirms that surgical debulking is a standard approach but often not curative with frequent recurrence.


MAXO:0000004

[PMID:34568242] [SUPPORT] Many therapeutic approaches have been attempted, including Sildenafil treatment, scleroembolization, laser therapy, and multiple debulking surgeries, but none of these were of benefit to our patient's clinical status. --- Explanation: Documents sclerotherapy (scleroembolization) as an attempted treatment modality in CLOVES syndrome management.


MAXO:0000126

[PMID:28627003] [SUPPORT] Patients with CLOVES syndrome have an increased risk of WT. Given the benefits of early detection and treatment, children with CLOVES syndrome should be considered for quarterly abdominal ultrasonography until age 7 years. Screening may be most beneficial for patients under 3 years of age. --- Explanation: Evidence-based screening recommendation from a cohort of 122 CLOVES patients with 3.3% Wilms tumor incidence.


hgnc:8975

[PMID:22658544] [SUPPORT] We identified mutations in PIK3CA in all six individuals, and mutant allele frequencies ranged from 3% to 30% in affected tissue from multiple embryonic lineages. Interestingly, these same mutations have been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity. We conclude that CLOVES is caused by postzygotic activating mutations in PIK3CA. --- Explanation: Landmark study identifying PIK3CA somatic mosaic mutations as the cause of CLOVES syndrome in all six patients studied, with mutant allele frequencies of 3-30% in affected tissues.

[PMID:34568242] [SUPPORT] PIK3CA-related cancers and PROS share almost the same PIK3CA mutational profile, with about 80% of mutations occurring at three hotspots, E542, E545, and H1047. These hotspot mutations show the most potent effect on enzymatic activation of PI3K and consequent downstream biological responses. --- Explanation: Confirms the three major hotspot mutations (E542, E545, H1047) account for about 80% of PIK3CA mutations in PROS/CLOVES.

[PMID:34074347] [SUPPORT] We have identified the first frameshift mutation in PIK3CA that causes CLOVES syndrome, which was confirmed to overactive PI3K/AKT/mTOR pathway by transient transfection assays. --- Explanation: Expands the mutational spectrum beyond missense mutations, demonstrating that frameshift mutations affecting the PIK3CA stop codon can also cause CLOVES syndrome through PI3K/AKT/mTOR pathway overactivation.


MONDO:0020630

[PMID:40548073] [SUPPORT] 80% of patients experiencing seizure onset before the age of one. The seizure types observed included epileptic spasms (93.3%) --- Explanation: In a cohort of 15 patients, 93.3% had epileptic spasms and 80% experienced seizure onset before age one, confirming this as the most frequent seizure type with infantile onset.

[PMID:40548073] [SUPPORT] 80% specifically diagnosed with infantile epileptic spasms syndrome (IESS). When combining data from this study and published studies, 66.7% of patients experienced seizure onset before the age of one, and 77.8% were diagnosed with IESS. --- Explanation: IESS is the predominant epileptic syndrome in PPP3CA-related DEE across combined cohort data.


MONDO:0020630

[PMID:28942967] [SUPPORT] we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA. --- Explanation: All six individuals in the original PPP3CA cohort had severe developmental delay (100% penetrance), establishing it as an obligate feature.

[PMID:40548073] [SUPPORT] All patients exhibited global developmental delay. --- Explanation: Confirms global developmental delay is present in all 15 patients in this cohort.


MONDO:0020630

[PMID:30455226] [SUPPORT] all 14 patients with de novo PPP3CA mutations documented to date have presented with obvious DD and ID regardless of the domain mutated --- Explanation: Review of all 14 patients reported by 2018 confirms universal presence of developmental delay and intellectual disability.


MONDO:0020630

[PMID:33963760] [SUPPORT] PPP3CA truncating variants clustered in the RD, causing more severe early-onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants. --- Explanation: Confirms that truncating variants in the regulatory domain cause severe refractory epilepsy.

[PMID:30455226] [SUPPORT] She was treated by levetiracetam 0.5 ml q12h, but seizures persisted --- Explanation: Case report demonstrating drug resistance with multiple antiepileptic drugs tried without achieving seizure control.


MONDO:0020630

[PMID:40548073] [SUPPORT] tonic seizures (46.7%) --- Explanation: Tonic seizures observed in 46.7% of a 15-patient cohort.


MONDO:0020630

[PMID:40548073] [SUPPORT] myoclonic seizures (46.7%) --- Explanation: Myoclonic seizures observed in 46.7% of a 15-patient cohort.


MONDO:0020630

[PMID:40548073] [SUPPORT] focal seizures (40.0%) --- Explanation: Focal seizures observed in 40% of a 15-patient cohort.


MONDO:0020630

[PMID:40548073] [SUPPORT] atypical absence seizures (13.3%) --- Explanation: Atypical absence seizures observed in 13.3% of a 15-patient cohort.


MONDO:0020630

[PMID:32593294] [SUPPORT] During the interictal stage, fragmented atypical hypsarrhythmia discharges appeared. --- Explanation: Case report demonstrating hypsarrhythmia pattern on EEG in a patient with PPP3CA frameshift variant.


MONDO:0020630

[PMID:32593294] [SUPPORT] mild hypotonia --- Explanation: Hypotonia reported as a feature in a PPP3CA case report.


MONDO:0020630

[PMID:32593294] [SUPPORT] Language delay was significant with meaningless sound and no word. --- Explanation: Demonstrates severe speech impairment in a PPP3CA case.


MONDO:0020630

[PMID:40548073] [SUPPORT] 45.5% of patients with CD variants had comorbid autism spectrum disorders, compared to 13% patients with RD variants. --- Explanation: ASD is more common with catalytic domain variants (45.5%) than regulatory domain variants (13%).


MONDO:0020630

[PMID:40548073] [SUPPORT] MRI abnormalities were noticed in 9 patients, including widened subarachnoid space, bilateral ventricular width, poor myelination of white matter, and dysplasia of the corpus callosum. --- Explanation: MRI abnormalities present in 9 of 15 patients, encompassing multiple types of structural brain changes.

[PMID:30455226] [SUPPORT] abnormalities in head MRI were observed, including brain dysplasia with cystic right basal ganglia, thin corpus callosum, and widened brain interval --- Explanation: Case report showing multiple structural brain abnormalities on MRI.


MONDO:0020630

[PMID:28942967] [SUPPORT] we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6) --- Explanation: Dysmorphic features observed in 3 of 6 individuals (50%) in the original PPP3CA cohort.


MONDO:0020630

[PMID:29432562] [INDIRECT EVIDENCE] [SUPPORT] Using a yeast model system, we showed that the catalytic and AI domain mutations visibly result in decreased and increased calcineurin signaling, respectively. These findings indicate that different functional effects of PPP3CA mutations are associated with two distinct disorders --- Explanation: Functional studies using yeast as a heterologous expression system demonstrated that catalytic domain mutations cause loss of function while auto-inhibitory domain mutations cause gain of function, explaining the two distinct clinical syndromes.

[PMID:28942967] [INDIRECT EVIDENCE] [SUPPORT] PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. --- Explanation: Establishes PPP3CA as encoding the calcineurin catalytic subunit alpha and its role in synaptic vesicle recycling, linking its loss of function to epilepsy.


MONDO:0020630


MONDO:0020630

[PMID:28942967] [INDIRECT EVIDENCE] [SUPPORT] PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. --- Explanation: Directly implicates calcineurin in synaptic vesicle recycling; loss of calcineurin disrupts this process and supports the role in epilepsy.


MAXO:0000167

[PMID:36158964] [SUPPORT] After being given multiple antiepileptic treatments with levetiracetam, adrenocorticotropic hormone (ACTH), prednisone, topiramate, and clonazepam, his seizures were not completely relieved. --- Explanation: Case demonstrating use of multiple AEDs with limited seizure control, typical of PPP3CA-related DEE.


MAXO:0030010

[PMID:30455226] [PARTIAL] She was then treated with a ketogenic diet. --- Explanation: Case report of ketogenic diet use; seizures persisted despite treatment.


MAXO:0000058

[PMID:36158964] [SUPPORT] After being given multiple antiepileptic treatments with levetiracetam, adrenocorticotropic hormone (ACTH), prednisone, topiramate, and clonazepam, his seizures were not completely relieved. --- Explanation: ACTH was used as part of multi-drug treatment for a patient with PPP3CA-related DEE, consistent with standard IESS management, though seizures were not fully controlled.


MAXO:0000058

[PMID:36158964] [PARTIAL] recurrent spasms and myoclonic seizures that could respond to vigabatrin --- Explanation: Vigabatrin showed some response in controlling spasms and myoclonic seizures in a PPP3CA case, though broader seizure control remained incomplete.


MAXO:0000079


hgnc:9314

[PMID:33963760] [SUPPORT] the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26-amino acid region in the regulatory domain (RD). --- Explanation: Demonstrates clustering of truncating variants in a narrow regulatory domain region.

[PMID:33963760] [SUPPORT] Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. --- Explanation: Functional evidence showing truncating variants produce mRNA but no stable protein, consistent with protein instability rather than NMD.

[PMID:30254215] [SUPPORT] Western blot experiments in patient's cells (EBV transformed lymphocytes and neuronal cells derived through reprogramming) indicate that despite normal mRNA abundance the protein expression level is strongly reduced both for the mutated and wild-type protein. By in vitro studies with recombinant protein expressed in E. coli we show that c.1324C>T (p.(Gln442Ter)) results in constitutive activation of the enzyme. --- Explanation: The p.Gln442Ter variant shows a paradoxical dual mechanism: recombinant protein studies reveal constitutive enzyme activation (truncation removes the auto-inhibitory domain), while patient-derived cells show strongly reduced protein expression from both mutant and wild-type alleles. The net effect in vivo is likely loss of function through protein instability despite the intrinsic hyperactivity of the truncated protein.


MONDO:0020630

[PMID:28942967] [SUPPORT] Five individuals with de novo PPP3CA mutations were identified among 4,760 trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 × 10-8) given the size and mutability of the gene. --- Explanation: Statistical evidence from trio exome sequencing of 4,760 families confirms de novo PPP3CA mutations are significantly enriched in neurodevelopmental disease, establishing autosomal dominant de novo inheritance.


MONDO:0011159

[PMID:23110709] [SUPPORT] Overall, mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%). --- Explanation: Systematic review demonstrates that COL11A2 mutations have the highest association with hearing impairment among Stickler-related collagen genes. Note that the 94.1% figure is derived from Stickler syndrome patients, not isolated non-syndromic deafness; it is cited here as supportive evidence for the auditory impact of COL11A2 mutations generally.

[PMID:10581026] [SUPPORT] In both families, deafness is non-progressive and predominantly affects middle frequencies. --- Explanation: Characterizes the DFNA13 hearing loss pattern as sensorineural, non-progressive, and mid-frequency.


MONDO:0011159

[PMID:10581026] [INDIRECT EVIDENCE] [SUPPORT] Mice with a targeted disruption of Col11a2 also were shown to have hearing loss. Electron microscopy of the tectorial membrane of these mice revealed loss of organization of the collagen fibrils. --- Explanation: Col11a2 knockout mice demonstrate hearing loss with ultrastructural tectorial membrane disorganization, providing a mechanistic link between collagen XI dysfunction and hearing impairment.

[PMID:10581026] [INDIRECT EVIDENCE] [SUPPORT] In both families, deafness is non-progressive and predominantly affects middle frequencies. --- Explanation: Establishes the characteristic mid-frequency hearing loss pattern of DFNA13, consistent with tectorial membrane involvement in frequency-specific cochlear tuning.


MONDO:0011159


MONDO:0011159

[PMID:16033917] [INDIRECT EVIDENCE] [SUPPORT] The P621T mutation of COL11A2 affects the Y position of the canonical -Gly-X-Y- repeat in collagens. It lies near the amino-terminus of the triple helical region and causes ARNSHL. --- Explanation: Identifies the molecular location of the first DFNB53 mutation within the collagen triple helix, establishing the pathogenic mechanism.

[PMID:25633957] [INDIRECT EVIDENCE] [SUPPORT] The novel p.Ala37Ser is the first missense mutation located in the NC4 domain of the COL11A2 protein. --- Explanation: Identifies a novel functional domain (NC4) affected by DFNB53 mutations, broadening understanding of COL11A2-related hearing loss mechanisms.


MAXO:0009030


MAXO:0009025


hgnc:2187

[PMID:16033917] [SUPPORT] This finding suggests that mutation type and location are critical determinants in defining the phenotype of COL11A2 associated diseases. --- Explanation: Establishes the genotype-phenotype correlation principle for COL11A2 mutations.

[PMID:25633957] [SUPPORT] Nonsense and frameshift mutations cause the very severe phenotypic effects associated with COL11A2 gene such as OSMED syndrome --- Explanation: Differentiates the severe syndromic phenotypes (truncating mutations) from the non-syndromic hearing loss (missense mutations).


MONDO:0011159

[PMID:10581026] [SUPPORT] We found two families (one American and one Dutch) with autosomal dominant, non-syndromic hearing loss to have mutations in COL11A2 that are predicted to affect the triple-helix domain of the collagen protein. --- Explanation: Original identification of COL11A2 as the DFNA13 gene, establishing autosomal dominant inheritance in two unrelated families.


MONDO:0011159

[PMID:16033917] [SUPPORT] Homozygosity for the P621T mutation of COL11A2 was present in all deaf persons in this family; this same variation was absent in 269 Iranian controls. --- Explanation: First identification of biallelic COL11A2 mutation causing autosomal recessive non-syndromic hearing loss in a consanguineous Iranian family.

[PMID:25633957] [SUPPORT] All homozygous individuals in those families had early onset profound hearing loss across all frequencies without syndromic findings. --- Explanation: Confirms DFNB53 with novel mutations in two additional consanguineous families, establishing the non-syndromic nature.


MONDO:0008490

[PMID:23110709] [SUPPORT] Overall, mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%). --- Explanation: Systematic review demonstrating 94.1% prevalence of hearing impairment with COL11A2 mutations.


MONDO:0008490

[PMID:10677296] [SUPPORT] an extremely flat face, hypoplasia of the mandible, a short nose with anteverted nares, and a flat nasal bridge. --- Explanation: Detailed craniofacial description of OSMED phenotype.


MONDO:0008490

[PMID:18381781] [SUPPORT] Radiographs of the affected adults showed severe polyarticular OA but did not reveal diagnostic evidence of an underlying skeletal dysplasia. --- Explanation: Demonstrates that early-onset osteoarthritis can be the dominant presentation of Stickler III, even masking the underlying dysplasia in adults.


MONDO:0008490

[PMID:37347055] [SUPPORT] He presented a phenotype highly suggestive of OSMED, including progressive sensorineural deafness, spondyloepiphyseal dysplasia with large epiphyses, platyspondyly, degenerative osteoarthritis, and sunken nasal bridge. --- Explanation: Clinical description of OSMED patient with platyspondyly as a cardinal feature.


MONDO:0008490

[PMID:18381781] [SUPPORT] the child's radiographs showed enlarged epiphyses with an advanced bone age. --- Explanation: Radiographic confirmation of enlarged epiphyses in a pediatric case.


MONDO:0008490

[PMID:10677296] [SUPPORT] profound sensorineural hearing loss, skeletal dysplasia with limb shortening and large epiphyses, cleft palate, an extremely flat face --- Explanation: Cleft palate listed among cardinal OSMED features across seven families.


MONDO:0008490

[PMID:10677296] [SUPPORT] a flat nasal bridge. --- Explanation: Flat nasal bridge documented in all OSMED families.


MONDO:0008490

[PMID:10677296] [SUPPORT] hypoplasia of the mandible --- Explanation: Mandibular hypoplasia documented across all OSMED families.


MONDO:0008490

[PMID:10677296] [SUPPORT] a short nose with anteverted nares --- Explanation: Short nose with anteverted nares documented across OSMED families.


MONDO:0008490

[PMID:37347055] [SUPPORT] A 29-year-old Chinese male was referred to our hospital for hearing loss and multiple joint pain. --- Explanation: Joint pain as a presenting complaint in an OSMED patient.


MONDO:0008490

[PMID:7859284] [INDIRECT EVIDENCE] [SUPPORT] an autosomal dominant form of Stickler syndrome, characterized by mild spondyloepiphyseal dysplasia, osteoarthritis, and sensorineural hearing loss, but no eye involvement, is caused by a splice donor site mutation resulting in "in-frame" exon skipping within the COL11A2 gene --- Explanation: Identifies the dominant-negative splice-site mutation mechanism and its phenotypic consequences in the original Stickler III family.

[PMID:7859284] [INDIRECT EVIDENCE] [SUPPORT] The results suggest that mutations in collagen XI genes are associated with a spectrum of abnormalities in human skeletal development and support the conclusion of others, based on studies of murine chondrodysplasia, that collagen XI is essential for skeletal morphogenesis. --- Explanation: Establishes collagen XI as essential for skeletal morphogenesis.


MONDO:0008490


MONDO:0008490

[PMID:10677296] [INDIRECT EVIDENCE] [SUPPORT] Of the 10 identified mutations, 9 are predicted to cause premature termination of translation, and 1 is predicted to cause an in-frame deletion. --- Explanation: Demonstrates that the overwhelming majority of OSMED mutations are null alleles, consistent with complete loss of alpha-2(XI) function.

[PMID:10677296] [INDIRECT EVIDENCE] [SUPPORT] All affected individuals had a remarkably similar phenotype: profound sensorineural hearing loss, skeletal dysplasia with limb shortening and large epiphyses, cleft palate, an extremely flat face, hypoplasia of the mandible, a short nose with anteverted nares, and a flat nasal bridge. --- Explanation: Comprehensive phenotypic description of OSMED across seven families, establishing the homogeneous severe phenotype.


MAXO:0000004


MAXO:0009030


MAXO:0009025


MAXO:0000079


hgnc:2187

[PMID:7859284] [SUPPORT] an autosomal dominant form of Stickler syndrome, characterized by mild spondyloepiphyseal dysplasia, osteoarthritis, and sensorineural hearing loss, but no eye involvement, is caused by a splice donor site mutation resulting in "in-frame" exon skipping within the COL11A2 gene, encoding the alpha 2(XI) chain of the quantitatively minor fibrillar collagen XI. --- Explanation: Original identification of COL11A2 as the gene responsible for non-ocular Stickler syndrome, with a dominant splice-site mutation.

[PMID:10677296] [SUPPORT] Individuals from four families, including three with consanguineous parents, were homozygous for mutations. Individuals from three other families, in whom parents were nonconsanguineous, were compound heterozygous. --- Explanation: Demonstrates both homozygous and compound heterozygous mutation patterns in OSMED across seven families.


MONDO:0008490

[PMID:7859284] [SUPPORT] an autosomal dominant form of Stickler syndrome, characterized by mild spondyloepiphyseal dysplasia, osteoarthritis, and sensorineural hearing loss, but no eye involvement, is caused by a splice donor site mutation resulting in "in-frame" exon skipping within the COL11A2 gene --- Explanation: Landmark Cell paper establishing that dominant COL11A2 splice-site mutations cause non-ocular Stickler syndrome with skeletal and auditory features.


MONDO:0008490

[PMID:10677296] [SUPPORT] We conclude that the OSMED phenotype is highly homogenous and results from homozygosity or compound heterozygosity for COL11A2 mutations, most of which are predicted to cause complete absence of alpha2(XI) chains. --- Explanation: Definitive study of seven OSMED families establishing autosomal recessive inheritance with loss-of-function COL11A2 mutations.


MONDO:0013453

[PMID:22065545] [SUPPORT] Night blindness was present in all patients but three, for whom a decrease of central vision and photophobia dominated. --- Explanation: Night blindness was present in the majority of CRB1-RP patients in this French cohort.


MONDO:0013453

[PMID:22065545] [SUPPORT] The onset of the disease occurs at birth and the characteristic features include non-recordable electroretinogram (ERG), nystagmus, sluggish or absent pupillary responses and oculo-digital reflexes --- Explanation: Nystagmus is described as a characteristic LCA feature in CRB1-associated disease.


MONDO:0013453

[PMID:36099972] [SUPPORT] Longitudinal analysis revealed a significant difference between baseline and follow-up best-corrected visual acuity in the 3 subcohorts. --- Explanation: Longitudinal data confirm progressive acuity decline across all CRB1 subtypes.

[PMID:28341475] [SUPPORT] In the RP group, median ages for reaching low vision, severe visual impairment, and blindness were 18, 32, and 44 years, respectively, with a visual acuity decline rate of 0.03 logarithm of the minimum angle of resolution per year. --- Explanation: Quantifies the rate and milestones of visual acuity decline in CRB1-RP.


MONDO:0013453

[PMID:22065545] [SUPPORT] 7/11 had typical bone spicule-shaped pigment migration within the peripheral retina whereas 4/11 had widespread clumped pigmentary changes of nummular appearance at the level of the retinal pigment epithelium --- Explanation: Documents two patterns of pigmentary change in CRB1-RP patients.


MONDO:0013453

[PMID:22065545] [SUPPORT] Hyperopia was noted for 6/11 patients including three for whom spherical equivalent was equal or above +5 diopters. --- Explanation: Hyperopia was present in over half of the French CRB1-RP cohort.


MONDO:0013453

[PMID:28341475] [SUPPORT] Cystoid fluid collections in the macula were found in 50% of RP patients. --- Explanation: Long-term follow-up documents high prevalence of macular cystic changes in CRB1-RP.

[PMID:22065545] [SUPPORT] Six of the patients displayed cystoid macular edema whereas the other five had macular thinning with loss of the outer retinal layers --- Explanation: Cystoid macular edema was present in approximately half of French CRB1 patients.


MONDO:0013453

[PMID:36099972] [SUPPORT] 24 with macular dystrophy (MD; 23%) --- Explanation: Identifies macular dystrophy as a distinct clinical presentation in 23% of the cohort.


MONDO:0013453

[PMID:22065545] [SUPPORT] Predisposition of the CRB1 patients to keratoconus --- Explanation: Literature review notes keratoconus as an associated feature of CRB1 mutations.


MONDO:0013453

[PMID:28341475] [SUPPORT] The annual VF decline rate was 5% in patients from the genetic isolate, which was significantly faster than in non-GI patients (P < 0.05). --- Explanation: Quantifies progressive visual field decline in CRB1-RP patients.


MONDO:0013453

[PMID:28341475] [SUPPORT] Full-field electroretinography responses were extinguished in 50% of patients, were pathologically attenuated without a documented rod or cone predominance in 30% of patients, and showed a rod-cone dysfunction pattern in 20% of RP patients. --- Explanation: Documents the spectrum of ERG findings in CRB1-RP from extinguished to attenuated responses.


MONDO:0013453

[PMID:12915475] [INDIRECT EVIDENCE] [SUPPORT] Shortened photoreceptor inner and outer segments are observed as early as 2 weeks after birth, suggesting a developmental defect in these structures rather than a degenerative process. --- Explanation: The rd8 mouse model demonstrates that CRB1 is essential for photoreceptor morphogenesis and OLM integrity.

[PMID:22065545] [INDIRECT EVIDENCE] [SUPPORT] CRB1 consists of 12 exons and exhibits alternative splicing at the 3' end, yielding two proteins of 1376 and 1406 amino acids --- Explanation: This review describes CRB1 protein structure including transmembrane and cytoplasmic domains critical for junction formation.


MONDO:0013453


MONDO:0013453

[PMID:12915475] [INDIRECT EVIDENCE] [SUPPORT] Photoreceptor degeneration is observed only within regions of retinal spotting, which is seen predominantly in the inferior nasal quadrant of the eye, and is caused by retinal folds and pseudorosettes. --- Explanation: Mouse model shows retinal disorganization with folds and pseudorosettes preceding degeneration.

[PMID:36099972] [INDIRECT EVIDENCE] [SUPPORT] The poor OCT lamination may have a degenerative component, as well as being congenital. --- Explanation: Clinical imaging suggests both developmental and degenerative contributions to retinal disorganization.


MONDO:0013453

[PMID:36099972] [INDIRECT EVIDENCE] [SUPPORT] Severe visual impairment was most frequent after 40 years of age for patients with RP and after 20 years of age for EOSRD/LCA. --- Explanation: Documents the differential timeline of severe visual impairment across CRB1 subtypes.

[PMID:28341475] [INDIRECT EVIDENCE] [SUPPORT] In the RP group, median ages for reaching low vision, severe visual impairment, and blindness were 18, 32, and 44 years, respectively, with a visual acuity decline rate of 0.03 logarithm of the minimum angle of resolution per year. --- Explanation: Quantifies the progressive visual loss trajectory in CRB1-RP patients.

[PMID:34320374] [INDIRECT EVIDENCE] [SUPPORT] Microperimetry showed a significant decrease in retinal sensitivity during follow-up and may be a more sensitive progression marker. --- Explanation: Prospective natural history data confirms ongoing retinal sensitivity decline in CRB1 patients.


hgnc:2343

[PMID:22065545] [SUPPORT] Mutations in the CRB1 gene are associated with variable phenotypes of severe retinal dystrophies, ranging from leber congenital amaurosis (LCA) to rod-cone dystrophy, also called retinitis pigmentosa (RP). --- Explanation: Comprehensive review establishing CRB1 as the causal gene for the spectrum of retinal dystrophies.

[PMID:22065545] [SUPPORT] This meta-analysis suggests that the differential phenotype of patients with CRB1 mutations is due to additional modifying factors rather than particular mutant allele combination. --- Explanation: Confirms CRB1 causality while noting phenotypic variability is driven by modifiers beyond allele type.

[PMID:12915475] [SUPPORT] Photoreceptor dysplasia and degeneration in Crb1 mutants strongly vary with genetic background, suggesting that the variability in phenotypes of human patients that carry mutations in CRB1 may be due to interactions with background modifiers in addition to allelic variations. --- Explanation: Mouse model confirms CRB1 as causal and supports the role of background modifiers in phenotypic variability.


MONDO:0013453

[PMID:22065545] [SUPPORT] Mutations in the CRB1 gene are associated with variable phenotypes of severe retinal dystrophies, ranging from leber congenital amaurosis (LCA) to rod-cone dystrophy, also called retinitis pigmentosa (RP). --- Explanation: This meta-analysis of CRB1 mutations confirms the autosomal recessive inheritance pattern across the retinal dystrophy spectrum.


MONDO:0014213

[PMID:31239556] [SUPPORT] Cognitive impairment was extremely variable, ranging from learning difficulties, normal IQ, and attending mainstream school or graduating from college in seven individuals to severe ID in three individuals. --- Explanation: Large cohort demonstrates highly variable cognitive impairment from normal IQ to severe intellectual disability.

[PMID:23746550] [SUPPORT] we now identified two de novo frameshift mutations and one de novo missense mutation in CTCF in individuals with intellectual disability, microcephaly, and growth retardation --- Explanation: Original identification of CTCF mutations in individuals with intellectual disability.


MONDO:0014213

[PMID:31239556] [SUPPORT] Walking age ranged from 12 months to three years, and age of first words from 12–18 months to lack of speech at age 12 years. --- Explanation: Cohort data showing variable but common developmental delay in motor and language milestones.


MONDO:0014213

[PMID:31239556] [SUPPORT] failure to thrive or feeding difficulties, often requiring tube feeding, occurred in 23 individuals --- Explanation: Feeding difficulties requiring tube feeding in approximately 64% of cohort (23/36).


MONDO:0014213

[PMID:31239556] [SUPPORT] (borderline) microcephaly in 12 individuals --- Explanation: Microcephaly observed in approximately one-third of affected individuals (12/36).

[PMID:23746550] [SUPPORT] we now identified two de novo frameshift mutations and one de novo missense mutation in CTCF in individuals with intellectual disability, microcephaly, and growth retardation --- Explanation: Microcephaly was part of the core phenotype in the original description.


MONDO:0014213

[PMID:31239556] [SUPPORT] Postnatal short stature was noted in 6 --- Explanation: Short stature in approximately 17% of the cohort (6/36).

[PMID:23746550] [SUPPORT] individuals with intellectual disability, microcephaly, and growth retardation --- Explanation: Growth retardation was part of the original phenotype description.


MONDO:0014213

[PMID:31239556] [SUPPORT] Behavioral anomalies such as autistic features, attention deficit and hyperactivity or aggressivity were common and reported in 24 individuals. --- Explanation: Behavioral abnormalities in approximately 67% of cohort (24/36).


MONDO:0014213

[PMID:31239556] [SUPPORT] muscular hypotonia were noted --- Explanation: Hypotonia mentioned as one of the range of anomalies observed in the cohort.


MONDO:0014213

[PMID:31239556] [SUPPORT] Cardiac defects occurred in 11 individuals --- Explanation: Cardiac defects in approximately 31% of cohort (11/36).


MONDO:0014213

[PMID:31239556] [SUPPORT] palatal anomalies such as cleft palate or high palate were present in 12 individuals --- Explanation: Palatal anomalies in approximately 33% of cohort (12/36).


MONDO:0014213

[PMID:31239556] [SUPPORT] Conductive and/or sensorineuronal hearing loss were reported in 10 --- Explanation: Hearing loss in approximately 28% of cohort (10/36).


MONDO:0014213

[PMID:31239556] [SUPPORT] Febrile or nonfebrile seizures or teeth anomalies occurred in four individuals --- Explanation: Seizures in approximately 11% of cohort (4/36).


MONDO:0014213

[PMID:23746550] [INDIRECT EVIDENCE] [SUPPORT] Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition. --- Explanation: Original discovery paper establishing that CTCF haploinsufficiency disrupts enhancer-promoter interactions critical for development and cognition.

[PMID:31239556] [INDIRECT EVIDENCE] [SUPPORT] Our extensive follow-up study does not indicate any clear correlation between nature and location of variants and clinical presentation. Furthermore, differentially expressed genes significantly overlapped between individuals with either missense or LGD variants --- Explanation: Large cohort study demonstrating that both missense and loss-of-function variants lead to similar functional consequences, supporting haploinsufficiency as the disease mechanism.


MONDO:0014213


MONDO:0014213

[PMID:38951485] [INDIRECT EVIDENCE] [SUPPORT] it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus --- Explanation: The R567W mutation causes specific chromatin structure alterations and dysregulation of protocadherin genes important for neuronal connectivity.


MONDO:0014213

[PMID:31239556] [INDIRECT EVIDENCE] [SUPPORT] RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation --- Explanation: Transcriptome analysis shows broad dysregulation of genes including those implicated in neurodevelopmental disorders.

[PMID:23746550] [INDIRECT EVIDENCE] [SUPPORT] Transcriptome analyses in all three individuals with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. --- Explanation: Initial transcriptome analysis showed CTCF mutations cause deregulation of signal transduction genes.


MONDO:0014213

[PMID:38951485] [INDIRECT EVIDENCE] [SUPPORT] This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. --- Explanation: Mouse model and human organoid studies show the R567W mutation causes premature neural progenitor depletion and accelerated GABAergic neuron maturation.


MAXO:0000950


MAXO:0000058


MAXO:0000079


HGNC.SYMBOL:CTCF

[PMID:31239556] [SUPPORT] The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. --- Explanation: Comprehensive description of the mutation spectrum in the largest reported cohort.

[PMID:23746550] [SUPPORT] we now identified two de novo frameshift mutations and one de novo missense mutation in CTCF --- Explanation: Original discovery of pathogenic CTCF variants.


MONDO:0043523

[PMID:39111871] [SUPPORT] She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction. --- Explanation: Documents renal tubular dysfunction as a key manifestation of chronic cadmium exposure.

[PMID:23800513] [SUPPORT] We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome. --- Explanation: Confirms acquired Fanconi syndrome from chronic cadmium toxicity.


MONDO:0043523

[PMID:20354761] [SUPPORT] An early and sensitive manifestation of chronic Cd renal toxicity, which can be useful in individual and population screening, is impaired reabsorption of low molecular weight proteins (LMWP) (also a receptor-mediated process in the proximal tubule) such as retinol binding protein (RBP). This so-called 'tubular proteinuria' is a good index of proximal tubular damage --- Explanation: Review identifies LMW proteinuria as the earliest and most sensitive marker of cadmium nephrotoxicity, suitable for population screening.

[PMID:19106433] [SUPPORT] Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function. --- Explanation: Confirms the specific LMW proteins excreted in cadmium nephrotoxicity: beta-2-microglobulin, retinol binding protein, and alpha-1-microglobulin.


MONDO:0043523

[PMID:31974582] [SUPPORT] Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia. --- Explanation: Confirms hypophosphataemic osteomalacia from occupational cadmium exposure.

[PMID:39111871] [SUPPORT] The shortening of height, bone deformities and fractures, abnormal bone metabolism suggesting osteomalacia, and renal anemia were also noted. --- Explanation: Documents osteomalacia with bone deformities and fractures in itai-itai disease.


MONDO:0043523

[PMID:23800513] [SUPPORT] We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome. --- Explanation: Case report of severe osteoporosis from chronic cadmium toxicity.

[PMID:18072106] [SUPPORT] We will present a case of cadmium induced peripheral neuropathy, nephropathy, and decreased bone density. --- Explanation: Confirms decreased bone density (osteoporosis) from cadmium exposure.


MONDO:0043523

[PMID:19341754] [SUPPORT] a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan. --- Explanation: Historical review identifies severe bone pain as the defining symptom of itai-itai disease, the archetypal chronic cadmium poisoning syndrome.

[PMID:7426480] [SUPPORT] during the last 12 years of his life the patient had suffered increasing disability from gross bone disease. Several bone biopsies and detailed metabolic studies showed typical severe osteomalacia --- Explanation: Case report documents 12 years of progressive bone pain and disability from cadmium-induced osteomalacia in an occupationally exposed worker.


MONDO:0043523

[PMID:31974582] [SUPPORT] Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia. --- Explanation: Confirms hypophosphataemia as the metabolic derangement underlying cadmium-induced osteomalacia.


MONDO:0043523

[PMID:39111871] [SUPPORT] She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction. --- Explanation: Documents chronic renal failure from cadmium exposure.


MONDO:0043523

[PMID:18072106] [SUPPORT] Cadmium is a neurotoxic and nephrotoxic heavy metal --- Explanation: Identifies cadmium as a neurotoxic heavy metal causing peripheral neuropathy.

[PMID:41453694] [SUPPORT] lead (Pb), cadmium (Cd), and arsenic (As) are pervasive environmental toxicants capable of entering the human body via multiple exposure routes, leading to profound neurotoxic effects. --- Explanation: Review of heavy metal neurotoxicity confirms cadmium produces profound neurotoxic effects through multiple exposure routes.


MONDO:0043523

[PMID:16933734] [SUPPORT] Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury. --- Explanation: Confirms cadmium as a cause of acute lung injury from inhalation.

[PMID:41000307] [SUPPORT] For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required. --- Explanation: Systematic review confirms severe pulmonary involvement requiring mechanical ventilation.


MONDO:0043523

[PMID:23800513] [INDIRECT EVIDENCE] [SUPPORT] Cadmium has a long biological half-life and there is no effective treatment for people who are exposed to it. --- Explanation: Confirms cadmium's long biological half-life contributing to progressive systemic accumulation.

[PMID:22349354] [INDIRECT EVIDENCE] [SUPPORT] In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets --- Explanation: Autopsy findings confirm systemic cadmium distribution to multiple organs.

[PMID:41000307] [INDIRECT EVIDENCE] [SUPPORT] The study also found that low iron stores exacerbate cadmium poisoning. --- Explanation: Confirms that iron deficiency enhances cadmium absorption via shared transport mechanisms.

[PMID:20204475] [INDIRECT EVIDENCE] [SUPPORT] uptake of free Cd(2+) has been demonstrated for the Fe(2+)/H(+) cotransporter divalent metal transporter 1. --- Explanation: Demonstrates that cadmium enters cells via DMT1, the shared iron transporter explaining iron-deficiency enhanced absorption.

[PMID:31704329] [INDIRECT EVIDENCE] [SUPPORT] this is the first study to reveal cadmium-binding proteins in real human blood plasma, which is extremely critical to our understanding of cadmium transportation and accumulation in human blood. --- Explanation: First identification of cadmium-binding proteins (apolipoprotein A-I) in human plasma, elucidating blood transport mechanisms.


MONDO:0043523

[PMID:25042840] [INDIRECT EVIDENCE] [SUPPORT] This half-life is partly as a result of metallothioneins (MTs), metal-binding proteins with a high affinity for Cd. --- Explanation: Confirms metallothionein as the primary cadmium-binding protein responsible for cadmium's long biological half-life.

[PMID:20354761] [INDIRECT EVIDENCE] [SUPPORT] The kidney is the main organ affected by chronic Cd exposure and toxicity. Cd accumulates in the kidney as a result of its preferential uptake by receptor-mediated endocytosis of freely filtered and metallothionein bound Cd (Cd-MT) in the renal proximal tubule. --- Explanation: Review confirms that hepatically-produced Cd-MT is filtered and taken up by the kidney, establishing the liver-to-kidney transfer pathway.


MONDO:0043523


MONDO:0043523

[PMID:20204475] [INDIRECT EVIDENCE] [SUPPORT] the multiligand endocytic receptors megalin and cubilin take up cadmium-metallothionein complexes via receptor-mediated endocytosis. --- Explanation: Demonstrates that megalin and cubilin receptors mediate the endocytic uptake of Cd-MT complexes in proximal tubule.

[PMID:34298880] [INDIRECT EVIDENCE] [SUPPORT] Cd2+ complexed to metallothionein (MT) (CdMT) is taken up through receptor-mediated endocytosis (RME) via the PT receptor megalin:cubilin, which is the predominant pathway for reuptake of filtered proteins in the kidney. --- Explanation: Confirms megalin:cubilin as the predominant receptor for Cd-MT uptake in proximal tubule.

[PMID:20354761] [INDIRECT EVIDENCE] [SUPPORT] Cd accumulates in the kidney as a result of its preferential uptake by receptor-mediated endocytosis of freely filtered and metallothionein bound Cd (Cd-MT) in the renal proximal tubule. Internalised Cd-MT is degraded in endosomes and lysosomes, releasing free Cd(2+) into the cytosol --- Explanation: Review details the full Cd-MT uptake pathway: glomerular filtration, receptor-mediated endocytosis, lysosomal degradation, and free Cd2+ release.

[PMID:25042840] [INDIRECT EVIDENCE] [SUPPORT] The high retention properties of the kidneys reside in proximal tubular cells that possess transport mechanisms for Cd-MT uptake, ultimately leading to more Cd accumulation. --- Explanation: Confirms proximal tubular cells possess specific transport mechanisms for Cd-MT uptake.


MONDO:0043523

[PMID:39111871] [INDIRECT EVIDENCE] [SUPPORT] She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction. --- Explanation: Documents advanced renal tubular dysfunction resulting from proximal tubular cell injury in chronic cadmium exposure.

[PMID:20354761] [INDIRECT EVIDENCE] [SUPPORT] Internalised Cd-MT is degraded in endosomes and lysosomes, releasing free Cd(2+) into the cytosol, where it can generate reactive oxygen species (ROS) and activate cell death pathways. --- Explanation: Review details the mechanism of tubular cell injury: lysosomal release of free Cd2+ generates ROS and activates apoptosis.


MONDO:0043523

[PMID:23800513] [INDIRECT EVIDENCE] [SUPPORT] We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome. --- Explanation: Case report confirming cadmium-induced acquired Fanconi syndrome with impaired tubular reabsorption.

[PMID:20576581] [INDIRECT EVIDENCE] [SUPPORT] Cd reduced the transcriptional expression of megalin and ClC5 and, at the same time, increased the degradation of megalin and ClC5 proteins via the lysosomal pathway in an in vitro model of renal proximal tubular cells. --- Explanation: Demonstrates the molecular mechanism: cadmium downregulates megalin and ClC5, the key receptors for protein reabsorption, explaining Fanconi syndrome.

[PMID:32244724] [INDIRECT EVIDENCE] [SUPPORT] The exposure of S1 and S2 cells to Cd at 1 and 3 µM for 3 days resulted in significant decreases in the uptakes of β2-MG and metallothionein but not in those of albumin or transferrin. --- Explanation: In vitro study directly demonstrates cadmium impairs endocytic uptake of low-molecular-weight proteins at nonlethal concentrations.

[PMID:20354761] [INDIRECT EVIDENCE] [SUPPORT] An early and sensitive manifestation of chronic Cd renal toxicity, which can be useful in individual and population screening, is impaired reabsorption of low molecular weight proteins (LMWP) --- Explanation: Review confirms impaired LMWP reabsorption as the earliest and most sensitive indicator of cadmium nephrotoxicity.


MONDO:0043523

[PMID:31974582] [INDIRECT EVIDENCE] [SUPPORT] Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia. --- Explanation: Confirms hypophosphataemia from renal phosphate wasting as the driver of cadmium-induced osteomalacia.


MONDO:0043523

[PMID:39111871] [INDIRECT EVIDENCE] [SUPPORT] She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction. --- Explanation: Documents progression to chronic renal failure from sustained cadmium-induced tubular damage.

[PMID:20354761] [INDIRECT EVIDENCE] [SUPPORT] Continued and heavy Cd exposure can progress to the clinical renal Fanconi syndrome, and ultimately to renal failure. --- Explanation: Review confirms the progressive nature of cadmium nephrotoxicity from tubular dysfunction to renal failure.


MONDO:0043523

[PMID:31974582] [INDIRECT EVIDENCE] [SUPPORT] Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia. --- Explanation: Confirms defective bone mineralization causing osteomalacia in cadmium-exposed workers.

[PMID:39111871] [INDIRECT EVIDENCE] [SUPPORT] The shortening of height, bone deformities and fractures, abnormal bone metabolism suggesting osteomalacia, and renal anemia were also noted. --- Explanation: Documents skeletal consequences of defective mineralization in itai-itai disease.


MONDO:0043523

[PMID:18072106] [INDIRECT EVIDENCE] [SUPPORT] We will present a case of cadmium induced peripheral neuropathy, nephropathy, and decreased bone density. --- Explanation: Documents decreased bone density from cadmium exposure, consistent with direct bone cell toxicity.


MONDO:0043523

[PMID:39381600] [INDIRECT EVIDENCE] [SUPPORT] liver SOD, GSH-Px, T-AOC and CAT levels were decreased, and MDA level was increased in Cd-treated goats, and 630 DEPs (up 326, down 304) in the livers of Cd-treated goats. --- Explanation: Proteomic study in goats confirms cadmium-induced hepatic antioxidant depletion.

[PMID:40164036] [INDIRECT EVIDENCE] [SUPPORT] exercise significantly decreased blood ALT and AST levels, alleviating oxidative stress in the liver by reducing MDA synthesis and enhancing SOD and GSH-PX activities. --- Explanation: Mouse model demonstrates cadmium-induced hepatic oxidative stress with depleted antioxidant enzymes.

[PMID:41188353] [INDIRECT EVIDENCE] [SUPPORT] Cd exposure altered hepatic lipid homeostasis via the perturbation of steatosis gene expression and lipid species abundances. Additionally, Cd exposure triggered a hepatic antioxidant response --- Explanation: Mouse model demonstrates cadmium triggers hepatic antioxidant response and disrupts lipid homeostasis, consistent with oxidative stress-driven liver injury.