MONDO:0018921

[PMID:24082939] [SUPPORT] Meckel-Gruber syndrome is a rare autosomal recessive lethal malformation characterized by typical manifestations of occipital encephalocele, bilateral polycystic kidneys and post axial polydactyly. --- Explanation: This review lists occipital encephalocele in the classic triad.

[PMID:8725749] [SUPPORT] Both babies showed the classical triad of this conditions: occipital encephalocele, cystic kidneys, and postaxial polydactyly of all four limbs. --- Explanation: A case report of two siblings documents occipital encephalocele in MKS.

[PMID:28374938] [SUPPORT] Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease. --- Explanation: A case report documents occipital encephalocele in MKS.

[PMID:38156946] [SUPPORT] Meckel syndrome (MKS) is the most severe form of an autosomal recessive ciliopathy and is clinically characterized by occipital encephalocele, severely polycystic kidneys, and postaxial polydactyly (toes). --- Explanation: Case report reiterates occipital encephalocele as part of the classic MKS triad.

[PMID:35352487] [SUPPORT] The pregnancy was terminated due to occipital meningocele and enlarged cystic dysplastic kidney revealed by ultrasonography. --- Explanation: Prenatal case report documents an occipital meningocele in suspected MKS.

[PMID:34821546] [SUPPORT] Antenatally detected occipital encephalocele and polycystic kidneys are a common presentation of ciliopathies like Joubert syndrome and Meckel Gruber syndrome --- Explanation: Prenatal case series reports occipital encephalocele among common MKS presentations.


MONDO:0018921

[PMID:24082939] [SUPPORT] Meckel-Gruber syndrome is a rare autosomal recessive lethal malformation characterized by typical manifestations of occipital encephalocele, bilateral polycystic kidneys and post axial polydactyly. --- Explanation: This review lists bilateral polycystic kidneys in the classic triad.

[PMID:8725749] [SUPPORT] Both babies showed the classical triad of this conditions: occipital encephalocele, cystic kidneys, and postaxial polydactyly of all four limbs. --- Explanation: A case report of two siblings documents cystic kidneys in MKS.

[PMID:28374938] [SUPPORT] Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease. --- Explanation: A case report documents multicystic renal disease in MKS.

[PMID:38156946] [SUPPORT] Meckel syndrome (MKS) is the most severe form of an autosomal recessive ciliopathy and is clinically characterized by occipital encephalocele, severely polycystic kidneys, and postaxial polydactyly (toes). --- Explanation: Case report reiterates severely polycystic kidneys as part of the classic MKS triad.

[PMID:35352487] [SUPPORT] The pregnancy was terminated due to occipital meningocele and enlarged cystic dysplastic kidney revealed by ultrasonography. --- Explanation: Prenatal case report documents enlarged cystic dysplastic kidney in suspected MKS.

[PMID:34821546] [SUPPORT] Antenatally detected occipital encephalocele and polycystic kidneys are a common presentation of ciliopathies like Joubert syndrome and Meckel Gruber syndrome --- Explanation: Prenatal case series notes polycystic/enlarged kidneys as a common MKS presentation.


MONDO:0018921

[PMID:24082939] [SUPPORT] Meckel-Gruber syndrome is a rare autosomal recessive lethal malformation characterized by typical manifestations of occipital encephalocele, bilateral polycystic kidneys and post axial polydactyly. --- Explanation: This review lists postaxial polydactyly in the classic triad.

[PMID:8725749] [SUPPORT] Both babies showed the classical triad of this conditions: occipital encephalocele, cystic kidneys, and postaxial polydactyly of all four limbs. --- Explanation: A case report of two siblings documents postaxial polydactyly in MKS.

[PMID:28374938] [SUPPORT] Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease. --- Explanation: A case report documents post-axial polydactyly in MKS.

[PMID:38156946] [SUPPORT] Meckel syndrome (MKS) is the most severe form of an autosomal recessive ciliopathy and is clinically characterized by occipital encephalocele, severely polycystic kidneys, and postaxial polydactyly (toes). --- Explanation: Case report reiterates postaxial polydactyly as part of the classic MKS triad.


MONDO:0018921

[PMID:25182137] [SUPPORT] frequent features include other central nervous system anomalies (51.4%), fibrotic/cystic changes of the liver (65.5% of cases with --- Explanation: This population-based study reports frequent hepatic fibrotic/cystic changes.


MONDO:0018921

[PMID:18603929] [SUPPORT] Death is mainly due to pulmonary hypoplasia. --- Explanation: This case report links MKS lethality to pulmonary hypoplasia.

[PMID:39412385] [SUPPORT] the fetus, which was found to have polyhydramnios, gastric dilatation, lung hypoplasia, and cystic formation with a diameter of 68*62mm in the abdomen --- Explanation: Case report documents lung hypoplasia in an MKS fetus.


MONDO:0018921

[PMID:19211713] [INDIRECT EVIDENCE] [SUPPORT] the underlying mutated gene, TMEM67, encodes transmembrane protein 67, also called meckelin (OMIM 609884), which is an integral protein of the renal epithelial cell and membrane of the primary cilium. --- Explanation: TMEM67/meckelin is an integral primary cilium membrane protein implicated in MKS3.


MONDO:0018921

[PMID:19776033] [INDIRECT EVIDENCE] [SUPPORT] The gene mutated in type 1 MKS encodes a protein associated with the base of the cilium in vertebrates and nematodes. --- Explanation: MKS1 encodes a protein associated with the ciliary base, supporting ciliary base dysfunction in MKS.


MONDO:0018921


MONDO:0018921

[PMID:19776033] [INDIRECT EVIDENCE] [SUPPORT] loss of Mks1 in vivo does not interfere with apical localization of epithelial basal bodies but rather leads to defective cilia formation in most, but not all, tissues. --- Explanation: Basal body localization is preserved while ciliogenesis fails in Mks1-deficient tissues.


MONDO:0018921

[PMID:19776033] [INDIRECT EVIDENCE] [SUPPORT] loss of Mks1 in vivo does not interfere with apical localization of epithelial basal bodies but rather leads to defective cilia formation in most, but not all, tissues. --- Explanation: Mks1 loss leads to defective cilia formation across tissues in vivo.


MONDO:0018921

[PMID:18513680] [INDIRECT EVIDENCE] [SUPPORT] Immunofluorescence staining of patient's fibroblast cells demonstrates that the cells lack cilia, providing evidence for the critical role of CC2D2A in cilia formation. --- Explanation: Patient fibroblasts lacking cilia link CC2D2A to cilia formation.


MONDO:0018921

[PMID:41165761] [INDIRECT EVIDENCE] [SUPPORT] the B9 complex interacted with and anchored TMEM67 to the TZ membrane. --- Explanation: Disruption of the B9-TMEM67 transition zone interaction underlies downstream axonemal defects.

[PMID:41165761] [INDIRECT EVIDENCE] [SUPPORT] Disruption of the B9-TMEM67 complex reduced posttranslational modifications of axonemal microtubules due to deregulation of tubulin-modifying enzymes within cilia. --- Explanation: B9 complex disruption impairs axonemal microtubule posttranslational modifications.


MONDO:0018921

[PMID:41165761] [INDIRECT EVIDENCE] [SUPPORT] B9 proteins localized to centrioles prior to ciliogenesis, where they facilitated the initiation of ciliogenesis. --- Explanation: B9 proteins are required for initiating ciliogenesis.


MONDO:0018921

[PMID:40436881] [INDIRECT EVIDENCE] [SUPPORT] Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis. --- Explanation: TMEM67 cleavage separates Wnt signaling from ciliogenesis in MKS.


MONDO:0018921

[PMID:40841990] [INDIRECT EVIDENCE] [SUPPORT] Our study reveals severe functional consequences, including TMEM17 destabilization and mislocalization, anomalies in cilium composition and function, and abrogation of Sonic Hedgehog signaling. --- Explanation: TMEM17 variants disrupt ciliary function and abrogate SHH signaling.


MONDO:0018921

[PMID:19776033] [INDIRECT EVIDENCE] [SUPPORT] Analysis of patterning in the neural tube and the limb demonstrates altered Hedgehog (Hh) pathway signaling underlies some MKS defects --- Explanation: Neural tube patterning defects in Mks1 mutants reflect altered Hedgehog signaling.

[PMID:34981460] [INDIRECT EVIDENCE] [SUPPORT] HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A were increased in mutated ZNF77 cells. --- Explanation: In vitro experiments from MKS cases link SHH signaling changes to MKS-associated genetic findings.


MONDO:0018921

[PMID:19776033] [INDIRECT EVIDENCE] [SUPPORT] Analysis of patterning in the neural tube and the limb demonstrates altered Hedgehog (Hh) pathway signaling underlies some MKS defects --- Explanation: Limb patterning defects in Mks1 mutants reflect altered Hedgehog signaling.


MAXO:0009072

[PMID:38459147] [SUPPORT] The study included 10 newborns with MKS associated with occipital encephalocele or meningocele, all of whom underwent surgical repair of the occipital sac. --- Explanation: Systematic review documents surgical repair of occipital encephalocele/meningocele in MKS.


MAXO:0009072

[PMID:38459147] [SUPPORT] 40% required shunting for hydrocephalus. --- Explanation: The systematic review reports shunting for hydrocephalus in MKS cases.


MAXO:0009072

[PMID:22134259] [SUPPORT] Acute cranial decompression in Meckel-Gruber syndrome and slit-ventricle syndrome with craniocephalic disproportion. --- Explanation: This report describes cranial decompression in the context of Meckel-Gruber syndrome.


MAXO:0001001

[PMID:33486889] [SUPPORT] CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches. --- Explanation: Review proposes exon skipping as a potential therapy for CC2D2A-associated MKS.


hgnc:7121

[PMID:19776033] [SUPPORT] The gene mutated in type 1 MKS encodes a protein associated with the base of the cilium in vertebrates and nematodes. --- Explanation: This mouse model study identifies the MKS1 gene underlying MKS type 1.


hgnc:28396

[PMID:19211713] [SUPPORT] In humans, the underlying mutated gene, TMEM67, encodes transmembrane protein 67, also called meckelin (OMIM 609884), which is an integral protein of the renal epithelial cell and membrane of the primary cilium. --- Explanation: This study identifies TMEM67 as the causal gene for MKS3.


hgnc:29253

[PMID:18513680] [SUPPORT] we identified the sixth locus and the fifth gene, CC2D2A (MKS6), behind MKS. --- Explanation: This study identifies CC2D2A as a causative MKS gene (MKS6).

[PMID:28374938] [SUPPORT] A medical exome analysis detected a heterozygous frameshift mutation, c.4582_4583delCG p.(Arg1528Serfs*17) in CC2D2A in the maternally derived allele. --- Explanation: This case report identifies pathogenic CC2D2A variants in MKS, including a frameshift allele.

[PMID:34981460] [SUPPORT] Whole exome sequencing identified a compound heterozygous of two novel variants of CEP290 and a heterozygous of a novel variant of CC2D2A. --- Explanation: Case series reports a novel CC2D2A variant in MKS fetuses.


hgnc:25018

[PMID:20512146] [SUPPORT] Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. --- Explanation: This study reports TMEM216 mutations causing Meckel syndrome.


hgnc:37234

[PMID:23349226] [SUPPORT] Mutations in TMEM231 cause Meckel-Gruber syndrome. --- Explanation: This report identifies TMEM231 as a Meckel-Gruber syndrome locus.


hgnc:28636

[PMID:21763481] [SUPPORT] We identified a homozygous c.301A>C (p.Ser101Arg) B9D2 mutation that segregates with MKS --- Explanation: This study reports a pathogenic B9D2 mutation segregating with MKS.


hgnc:24123

[PMID:21763481] [SUPPORT] Mice lacking B9d1 displayed polydactyly, kidney cysts, ductal plate malformations, and abnormal patterning of the neural tube, concomitant with compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal transduction. --- Explanation: Loss of B9d1 causes MKS-like phenotypes with ciliary dysfunction in model organisms.

[PMID:40933483] [SUPPORT] Compound heterozygous missense and intronic variants in B9D1 contribute to a recurrent Meckel syndrome pedigree. --- Explanation: This case report identifies pathogenic B9D1 variants in a recurrent MKS pedigree.


hgnc:29021

[PMID:17705300] [SUPPORT] Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome. --- Explanation: This study identifies CEP290 loss-of-function mutations as a cause of Meckel-Gruber syndrome.

[PMID:35352487] [SUPPORT] compound heterozygous mutations of CEP290 c.3175dup and CEP290 c.1201dup were detected through WES. --- Explanation: Prenatal case report identifies compound heterozygous CEP290 variants in suspected MKS.

[PMID:34981460] [SUPPORT] Whole exome sequencing identified a compound heterozygous of two novel variants of CEP290 and a heterozygous of a novel variant of CC2D2A. --- Explanation: Case series reports novel CEP290 variants in MKS fetuses.


hgnc:29168

[PMID:17558409] [SUPPORT] we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS --- Explanation: This study reports RPGRIP1L mutations in Meckel syndrome.


hgnc:7907

[PMID:18371931] [SUPPORT] Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. --- Explanation: This study links NPHP3 loss of function to a Meckel-Gruber-like syndrome in humans.


hgnc:25774

[PMID:21462283] [SUPPORT] A TCTN2 mutation defines a novel Meckel Gruber syndrome locus. --- Explanation: This report identifies TCTN2 (MKS8) as a Meckel syndrome locus.


hgnc:14432

[PMID:26729329] [SUPPORT] These analyses identified a putative intragenic AHI1 deletion that included three exons spanning at least 3.4 kb and an intergenic MPP4 to TMEM237 deletion that included exons spanning at least 21.5 kb. --- Explanation: CNV analysis in a MKS/JBTS referral cohort identified a TMEM237 deletion consistent with MKS involvement.


hgnc:28128

[PMID:26123494] [SUPPORT] This study shows that known MKS loci account for the overwhelming majority of MKS cases but additional loci exist including MKS13 caused by TMEM107 mutation. --- Explanation: This study defines TMEM107 mutations as a Meckel syndrome locus (MKS13).


hgnc:20652

[PMID:31411728] [SUPPORT] We describe the second family with MKS due to a homozygous variant in B9D2 and fifth family with bi-allelic variant in TXNDC15. --- Explanation: This study validates MKS causation by biallelic TXNDC15 variants.

[PMID:38156946] [SUPPORT] We report the case of a homozygous mutation in the TXNDC15 gene, causing MKS14 in the Chinese population. --- Explanation: Case report identifies a homozygous TXNDC15 mutation causing MKS14.

[PMID:39304719] [SUPPORT] Biallelic TXNDC15 variants have been reported in six individuals of Meckel syndrome (MKS) with perinatal lethal phenotypes --- Explanation: This report summarizes prior MKS cases with biallelic TXNDC15 variants, supporting causation.

[PMID:41518077] [SUPPORT] Homozygous Txndc15mt/mt embryos displayed the complete MKS phenotype-fetal lethality, exencephaly, omphalocele, post-axial polydactyly, and polycystic kidneys-together with markedly reduced TXNDC15 protein in brain, liver, and kidney. --- Explanation: Mouse model confirms TXNDC15 loss produces an MKS phenotype.


hgnc:26623

[PMID:40841990] [SUPPORT] we report two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts, in whom exome sequencing identified a founder homozygous missense variant (Arg94Trp) in TMEM17 --- Explanation: Case report expands TMEM17-associated phenotypes to include MKS.


hgnc:30497

[PMID:21552264] [SUPPORT] KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. --- Explanation: This study suggests KIF7 variants can contribute to ciliopathy phenotypes, supporting a modifier role within the MKS/JBTS spectrum.


MONDO:0015277


MAXO:0000004


MAXO:0000058

[PMID:32846061] [SUPPORT] In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). --- Explanation: The LIBRETTO-001 trial demonstrated that selpercatinib achieves 73% response rate and 92% 1-year PFS in treatment-naive RET-mutant MTC patients.


NCIT:C134987

[PMID:32846061] [INDIRECT EVIDENCE] [SUPPORT] In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). --- Explanation: The LIBRETTO-001 trial demonstrated that selpercatinib achieves 73% response rate and 92% 1-year PFS in treatment-naive RET-mutant MTC patients.


MAXO:0000058


NCIT:C132295


CHEBI:49960


CHEBI:72317


HGNC.SYMBOL:RET


MONDO:0015277

[PMID:40800658] [SUPPORT] Medullary thyroid carcinoma (MTC) is rare and originates from parafollicular C --- Explanation: Abstract indicates that MTC originates from parafollicular C cells.


MONDO:0850197


MONDO:0850197

[PMID:35489737] [INDIRECT EVIDENCE] [SUPPORT] SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway. --- Explanation: This abstract explicitly states that SHH tumors have GLI1/GLI2/SUFU/PTCH1 alterations that constitutively activate SHH signaling.


MAXO:0000014


MAXO:0000647


CHEBI:66903


CHEBI:90863


HGNC.SYMBOL:PTCH1


HGNC.SYMBOL:SMO


HGNC.SYMBOL:SUFU


HGNC.SYMBOL:GLI2


HGNC.SYMBOL:MYCN


HGNC.SYMBOL:TP53


HGNC.SYMBOL:TERT


MONDO:0850197

[PMID:41544627] [SUPPORT] Medulloblastoma, the most common malignant brain tumor of childhood, exhibits --- Explanation: Abstract states medulloblastoma is the most common malignant brain tumor of childhood.


MONDO:0850196


MONDO:0850196

[PMID:40967259] [INDIRECT EVIDENCE] [SUPPORT] nearly all cases harbor either somatic CTNNB1 mutations or germline APC mutations. --- Explanation: This abstract sentence supports that WNT-activated medulloblastomas are driven by CTNNB1 or APC mutations.


MAXO:0000004


MAXO:0000014

[PMID:32743560] [SUPPORT] Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival --- Explanation: Supports the rationale for radiation de-escalation trials in WNT-activated medulloblastoma due to excellent survival.


MAXO:0000647

[PMID:32743560] [SUPPORT] Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse --- Explanation: Documents the role of maintenance chemotherapy with cyclophosphamide in preventing relapse in WNT-activated medulloblastoma.


HGNC.SYMBOL:CTNNB1

[PMID:33405951] [SUPPORT] Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors --- Explanation: Documents the high frequency of CTNNB1 mutations (96%) in WNT-activated medulloblastoma from the SJMB03 international phase III trial.


HGNC.SYMBOL:APC


HGNC.SYMBOL:DDX3X

[PMID:22820256] [SUPPORT] Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations --- Explanation: Original exome sequencing study identifying DDX3X as recurrently mutated in medulloblastoma, often concurrent with CTNNB1 mutations in WNT tumors.

[PMID:33405951] [SUPPORT] Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors --- Explanation: Documents the frequency of DDX3X mutations (37%) in WNT-activated medulloblastoma from the SJMB03 trial.


HGNC.SYMBOL:SMARCA4

[PMID:33405951] [SUPPORT] Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors --- Explanation: Documents the frequency of SMARCA4 mutations (24%) in WNT-activated medulloblastoma from the SJMB03 trial.


HGNC.SYMBOL:Monosomy 6

[PMID:17172831] [SUPPORT] loss of chromosome 6 was exclusively observed in Wnt/Wg-active tumors, but not in Wnt/Wg-negative cases (8/13 vs. 0/19; p = 0.0001) --- Explanation: Early molecular study demonstrating exclusive association of chromosome 6 loss with WNT pathway-active medulloblastomas.

[PMID:21267586] [SUPPORT] Monosomy 6 was strongly associated with WNT tumors --- Explanation: Confirms strong association of monosomy 6 with WNT molecular subgroup.


MONDO:0850110

[PMID:38779794] [SUPPORT] A 30-year-old female patient presented with a swelling of a cervical left lymph node measuring 1x3 cm, which had been presenting for three weeks. Lymph node excision revealed a metastasis of a malignant melanoma. --- Explanation: The swollen lymph nodes indicating metastasis, with the subject having melanoma, supports the statement of lymphadenopathy as an occasional systemic phenotype of melanoma-in-congenital-melanocytic-nevus.

[PMID:14750241] [PARTIAL] Melanocytic nevi occurring in lymph nodes create diagnostic difficulty by mimicking metastases. Few studies describe nodal nevi in sentinel lymph nodes (SLNs) excised for melanoma. --- Explanation: While this source discusses lymph nodes in relation to melanoma, the focus is more on diagnostic difficulty rather than a clear statement of lymphadenopathy as a phenotype.

[PMID:11902552] [SUPPORT] Lymph-node metastasis is an indicator of poor prognosis for patients with melanoma. --- Explanation: Lymph-node metastasis being a poor prognosis indicator supports the link between swollen lymph nodes and metastasis in melanoma patients, supporting the statement.

[PMID:18481261] [PARTIAL] Malignant melanomas of the skin primarily metastasize to lymph nodes, and the detection of sentinel lymph node metastases serves as an important prognostic parameter. --- Explanation: This source confirms the occurrence of lymph node metastasization in melanoma but does not specifically address it in the context of congenital melanocytic nevus.


MONDO:0850110

[PMID:29971818] [PARTIAL] We report a 6-year-old child with molluscum contagiosum infection arising within an intermediate melanocytic congenital nevus of the thigh, associated with itching and occasional bleeding. --- Explanation: The literature supports that itching can be associated with a congenital melanocytic nevus, but it does not specifically link this to melanoma. Therefore, the statement is only partially supported.


MONDO:0850110


MONDO:0850110

[PMID:16750612] [INDIRECT EVIDENCE] [SUPPORT] The most exciting finding is the discovery of oncogenic BRAF mutations in both malignant melanoma and melanocytic nevi. This finding indicates that activation of the mitogen-activated protein kinase pathway may be a critical initiating step of melanocytic neoplasia. --- Explanation: This study supports the role of BRAF mutations in the pathophysiology of melanoma in melanocytic nevi, including congenital cases.

[PMID:28110826] [INDIRECT EVIDENCE] [PARTIAL] Congenital melanocytic nevus syndrome (CMNS) is the result of an abnormal proliferation of melanocytes in the skin and central nervous system caused by progenitor-cell mutations during embryonic development. Mutations in the NRAS gene have been detected in many of these cells. --- Explanation: This reference covers NRAS mutations in congenital melanocytic nevus syndrome but does not mention BRAF mutations.

[PMID:32100974] [INDIRECT EVIDENCE] [SUPPORT] Melanomas developing on pre-existing congenital or acquired nevi are usually of the superficial spreading subtype and harbor the BRAFV600E mutation. --- Explanation: This study supports the presence of BRAF mutations in melanomas associated with congenital melanocytic nevi.

[PMID:31111470] [INDIRECT EVIDENCE] [SUPPORT] NRAS mosaicism was found in 68%, BRAF in 7% and double wild-type in 25% of cases of CMN. NRAS was the commonest mutation in all sizes of CMN. --- Explanation: This comprehensive review provides evidence of both NRAS and BRAF mutations in congenital melanocytic nevi, which supports their role in the development of melanoma.


MAXO:0000004

[PMID:33010324] [NO_EVIDENCE] Segmental excision of congenital melanocytic nevus by multiple incisions.

[PMID:11079795] [SUPPORT] An excisional biopsy is the appropriate diagnostic procedure for a skin lesion suspected of being a melanoma. --- Explanation: Excision is recommended for diagnosing and treating melanoma.

[PMID:14379056] [SUPPORT] The tenet of excision and dissection in continuity where feasible of the primary melanoma and the regional lymph nodes is reemphasized. --- Explanation: This reference supports the surgical excision of melanoma, including melanoma arising in congenital melanocytic nevus.

[PMID:22980259] [PARTIAL] Treatment of congenital melanocytic nevi (CMN) is generally undertaken for 2 reasons: (1) to reduce the chances of cutaneous malignant melanoma and (2) for cosmetic reasons. --- Explanation: Excision is one of several treatments considered but the exact treatment for melanoma is not specified.

[PMID:1615092] [SUPPORT] The child underwent a complete surgical excision of this lesion with immediate coverage by partial-thickness skin grafts. --- Explanation: The reference describes a case where melanoma in a congenital melanocytic nevus was treated by surgical excision.

[PMID:15817400] [SUPPORT] Surgical excision may be considered for cosmetic purposes and to reduce the small risk for the development of malignancy within each lesion. --- Explanation: Surgical excision is recommended for congenital melanocytic nevus to mitigate cancer risk.


MAXO:0000058

[PMID:27453302] [SUPPORT] In recent years systemic targeted- and immunotherapy have proven to be beneficial in advanced melanoma and could be a promising strategy for (neo)adjuvant treatment of patients with resectable high risk melanomas as well. --- Explanation: This indicates that immunotherapy, which stimulates the immune system to target melanoma cells, could be beneficial for melanoma in high-risk patients, supporting the statement.

[PMID:16762733] [SUPPORT] Melanoma has been widely studied as a target for immunotherapy because it has been considered more susceptible to immune attack than other tumors... This article reviews the recent clinical results of trials exploring different immunotherapy strategies against melanoma. --- Explanation: The literature supports that immunotherapy is used to target melanoma cells, supporting the statement.

[PMID:36435868] [PARTIAL] Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for patients with metastatic melanoma; however, there remains an unmet clinical need for alternative treatment options for those patients who are either intolerant or refractory to immunotherapy. --- Explanation: This suggests that while immunotherapy is used, it is not universally effective for all patients, therefore partially supporting the statement.


MAXO:0000058

[PMID:24880943] [SUPPORT] In cutaneous melanomas with BRAF V600 mutations the selective RAF inhibitors, vemurafenib and dabrafenib, and the MEK inhibitor, trametinib, have demonstrated survival benefits. --- Explanation: This reference indicates that targeted therapies, such as BRAF inhibitors, are effective in treating melanomas with specific genetic mutations.

[PMID:30792255] [PARTIAL] We present the case of a 7-year-old girl with a giant congenital melanocytic nevus that had an AKAP9-BRAF fusion and was treated with trametinib, which resulted in rapid resolution of the patient's lifelong, intractable pain and pruritus as well as dramatic improvement in the extent of her nevus. --- Explanation: This reference supports the use of trametinib, a targeted therapy, in treating a congenital melanocytic nevus with a specific genetic mutation, though the primary outcome discussed is symptom relief rather than melanoma treatment.


MAXO:0000014

[PMID:8977557] [PARTIAL] Although surgery remains the treatment of choice for the vast majority of localized melanomas, available data indicate that radiation therapy is a viable alternative for a few subsets of patients in whom surgery would result in cosmetic or functional deformity. --- Explanation: Radiation therapy is recommended in certain circumstances, but is not the primary treatment method for localized melanomas which include melanomas arising from congenital melanocytic nevi.

[PMID:12609784] [NO_EVIDENCE] Lasers should only be regarded as a treatment option for GCMN that cannot be surgically excised. --- Explanation: The provided abstract discusses laser therapy as an alternative to surgery for GCMN but does not mention radiation therapy.

[PMID:28092363] [NO_EVIDENCE] This review will focus exclusively on genetically engineered mouse models of UVR-induced melanoma. --- Explanation: The provided abstract is about mouse models for UV-induced melanoma and does not discuss the treatment of melanomas arising from congenital melanocytic nevi with radiation therapy.

[PMID:19880040] [PARTIAL] Adjuvant therapies such as chemotherapy, immunotherapy, and radiation therapy can be used in advanced cases. --- Explanation: Radiation therapy is listed as an adjuvant treatment in advanced pediatric melanoma cases, which can include those arising from conditions like congenital melanocytic nevi.

[PMID:29958291] [PARTIAL] Radiation therapy is a useful and standard tumor treatment strategy... Some strategies are focused on enhancement of accuracy in ionizing radiation delivery and on the generation of greater radiation beams... --- Explanation: The abstract discusses radiation therapy and its enhancement but does not specifically address radiation therapy for melanomas originating from congenital melanocytic nevi.


MAXO:0000647

[PMID:22980259] [PARTIAL] Treatment of congenital melanocytic nevi (CMN) is generally undertaken for 2 reasons: (1) to reduce the chances of cutaneous malignant melanoma and (2) for cosmetic reasons. Over the past century, a large number of treatments for CMN have been described in the literature. These include excision, dermabrasion, curettage, chemical peels, radiation therapy, cryotherapy, electrosurgery, and lasers. Only low-level evidence supporting these approaches is available, and large randomized controlled trials have not been published. --- Explanation: Although chemotherapy is not explicitly mentioned, the focus on various treatments for melanoma suggests that a range of therapeutic approaches exists.

[PMID:27268913] [PARTIAL] Malignant melanoma represents a neoplasm stemming from melanocytes or the cells that develop from melanocytes. Melanocytes, pigment-producing cells, arise from the neural crest and migrate to their final destinations in the skin, uveal tract, meninges, and mucosa. Most melanocytes are found at the epidermal-dermal junction of the skin, and the vast majority of melanocytes arise from cutaneous sites. Cancerous growths develop when unrepaired DNA damage to skin cells (most often caused by ultraviolet radiation from sunshine or tanning beds) triggers mutations (genetic defects) that lead the skin cells to multiply rapidly and form malignant tumours. --- Explanation: While chemotherapy is an established approach for treating malignant melanoma, this reference does not provide explicit information about its use specifically in congenital melanocytic nevus-related melanoma.


HGNC.SYMBOL:BRAF

[PMID:16750612] [SUPPORT] The most exciting finding is the discovery of oncogenic BRAF mutations in both malignant melanoma and melanocytic nevi. --- Explanation: The excerpt indicates that BRAF mutations are found in both malignant melanoma and melanocytic nevi, supporting the statement.

[PMID:37156689] [SUPPORT] A lot of congenital melanocytic nevi (CMN) carry the somatic mutation in the oncogene BRAF V600E. --- Explanation: The excerpt clearly states the presence of BRAF mutations in congenital melanocytic nevi.

[PMID:31111470] [SUPPORT] BRAF is confirmed as a much rarer cause of multiple CMN. --- Explanation: Although BRAF is a less common mutation in CMN, its presence still supports the statement.

[PMID:36085074] [SUPPORT] Mutations in NRAS have been previously detected in GCMN, but mutations in BRAF are generally lacking in the Chinese population. --- Explanation: The excerpt suggests the presence of BRAF mutations in GCMN, though less frequent in the Chinese population.


HGNC.SYMBOL:NRAS

[PMID:33851646] [SUPPORT] NRAS mutant melanoma arising in a giant congenital melanocytic nevus in an infant. --- Explanation: This reference directly describes a case of NRAS mutant melanoma arising in the context of giant congenital melanocytic nevus.

[PMID:31111470] [SUPPORT] Multiple congenital melanocytic naevi (CMN) have been shown to be caused by NRAS mosaic mutations in 70-80% of cases. --- Explanation: This reference provides statistical data supporting the association between NRAS mutations and congenital melanocytic nevi.


HGNC.SYMBOL:TERT


HGNC.SYMBOL:CDKN2A


HGNC.SYMBOL:TP53


HGNC.SYMBOL:PTEN


HGNC.SYMBOL:MET


HGNC.SYMBOL:RAF1


ECTO:0000006

[PMID:32281145] [SUPPORT] Both UVB and UVA are physiologically responsible for a plethora of skin ailments, including skin cancers. The UVR is readily absorbed by the genomic DNA of skin cells, causing DNA bond distortion and UV-induced DNA damage. --- Explanation: This excerpt supports the statement that UV radiation from sunlight causes DNA damage, which is relevant to Melanoma_in_Congenital_Melanocytic_Nevus.

[PMID:35298329] [SUPPORT] Sunbed use is responsible for a significant proportion of both melanoma and non-melanoma skin cancers, especially in patients exposed to this practice in early life, premature skin ageing, immunosuppression, skin burns, and eye damage. --- Explanation: This supports the statement by indicating that artificial tanning devices, such as tanning beds, contribute to the development of skin cancers, including melanoma, through exposure to UV radiation.

[PMID:30113042] [SUPPORT] The main etiologic factor is ultraviolet radiation, from the sun as well as artificial tanning devices. --- Explanation: This explains that UV radiation from both natural sunlight and artificial tanning devices is a major factor in melanoma development.

[PMID:25252745] [SUPPORT] UV radiation is a carcinogen known to play a role in the development of non-melanoma and melanoma skin cancers. Acute and chronic exposure to UV radiation causes clinical and biological effects that promote the unregulated proliferation of skin cells. --- Explanation: This information supports the statement by highlighting the role of UV radiation in the development of melanoma, through DNA damage.


MONDO:0850110

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


MONDO:0007969

[PMID:39135018] [SUPPORT] recurrent edema, facial palsies, and nerve dysfunctions often associated with the plicata tongue --- Explanation: Confirms recurrent facial edema as a characteristic phenotype of MRS

[PMID:31466978] [SUPPORT] he presented the classic triad of Melkersson-Rosenthal syndrome which includes recurrent orofacial oedema, facial nerve palsy and fissured tongue --- Explanation: Establishes recurrent orofacial edema as part of the classic clinical triad


MONDO:0007969

[PMID:31466978] [SUPPORT] recurrent facial nerve palsy since the age of 10 years --- Explanation: Documents the recurrent nature of facial nerve paralysis in MRS patients

[PMID:40255708] [SUPPORT] CG can occur as an isolated condition or as part of Melkersson-Rosenthal syndrome, which also includes facial paralysis and a fissured tongue --- Explanation: Confirms facial paralysis as a component of the MRS triad


MONDO:0007969

[PMID:31466978] [SUPPORT] Physical examination revealed lip swelling and lingua plicata. Thus, he presented the classic triad of Melkersson-Rosenthal syndrome --- Explanation: Confirms fissured tongue (lingua plicata) as part of the classic MRS triad

[PMID:40255708] [SUPPORT] Melkersson-Rosenthal syndrome, which also includes facial paralysis and a fissured tongue --- Explanation: Establishes lingual swelling as a key phenotype of MRS


MONDO:0007969

[PMID:37510386] [PARTIAL] Migraine is a common neurological disorder... A family in which two sisters displayed recurrent migraines, one of which presented recurrent facial palsy and had clinical diagnosis of MRS. --- Explanation: Documents rare association of migraine with MRS in a family with SCN1A variants, suggesting potential genetic overlap


MONDO:0007969

[PMID:39135018] [INDIRECT EVIDENCE] [SUPPORT] Melkersson-Rosenthal syndrome (MRS) is a rare neuro-mucocutaneous disorder characterized by recurrent edema, facial palsies, and nerve dysfunctions often associated with the plicata tongue. --- Explanation: Establishes the clinical phenotype and neuromucocutaneous involvement characteristic of MRS

[PMID:30627963] [INDIRECT EVIDENCE] [SUPPORT] Granulomatous lesions of the orofacial region are a heterogeneous group of disorders characterized by a granulomatous reaction to a variety of stimuli. --- Explanation: Provides context for the granulomatous nature of orofacial pathology including MRS


MONDO:0007969


MONDO:0007969

[PMID:32782477] [INDIRECT EVIDENCE] [SUPPORT] IL-12 and IL-23 are linked to the production of IFN-γ, a pivotal mediator of inflammation in peripheral tissues, including orofacial mucosa, by promoting multiple proinflammatory cytokines. --- Explanation: Identifies the IL-12/23 and IFN-γ cytokine pathways implicated in orofacial granulomatous inflammation


MONDO:0007969

[PMID:32782477] [INDIRECT EVIDENCE] [SUPPORT] IL-12 and IL-23 are linked to the production of IFN-γ, a pivotal mediator of inflammation in peripheral tissues, including orofacial mucosa, by promoting multiple proinflammatory cytokines. --- Explanation: Supports the lymphatic dysfunction mechanism through inflammatory cytokine effects on endothelial function


MAXO:0000640

[PMID:32782477] [SUPPORT] Oral or locally injected corticosteroids (triamcinolone) are the initial therapeutic option. --- Explanation: Establishes intralesional corticosteroid injection as first-line therapy for MRS-associated granulomatous cheilitis


MAXO:0000640

[PMID:39135018] [SUPPORT] A comprehensive diagnosis and multidisciplinary treatment approach including surgery, local injections, and oral medication were implemented, resulting in a favorable prognosis. --- Explanation: Supports the use of systemic medication (oral corticosteroids) as part of multidisciplinary MRS management


MAXO:0000058

[PMID:32782477] [SUPPORT] Reported evidence indicates treatment with an anti-TNF agent (mainly infliximab) is the most recommended therapeutic option after failure of conventional treatments. --- Explanation: Establishes infliximab as a validated TNF-α blockade strategy for refractory granulomatous cheilitis


MAXO:0000058

[PMID:32782477] [SUPPORT] ustekinumab, a monoclonal antibody against interleukins 12/23, with proven efficacy in CD and psoriasis, is attractive. The present study is the second to report on the effectiveness of ustekinumab for inducing remission of severe and recurrent granulomatous cheilitis in patients with CD. --- Explanation: Demonstrates efficacy of IL-12/23 blockade in treating refractory MRS-associated granulomatous cheilitis


MAXO:0000950

[PMID:39135018] [SUPPORT] A comprehensive diagnosis and multidisciplinary treatment approach including surgery, local injections, and oral medication were implemented, resulting in a favorable prognosis. --- Explanation: Emphasizes the importance of multidisciplinary supportive care in MRS management


HGNC.SYMBOL:TNF-α pathway involvement

[PMID:32782477] [SUPPORT] Reported evidence indicates treatment with an anti-TNF agent (mainly infliximab) is the most recommended therapeutic option after failure of conventional treatments. --- Explanation: Demonstrates TNF-α involvement in MRS through effective therapeutic targeting with anti-TNF agents


HGNC.SYMBOL:IFN-γ pathway involvement in autoimmune/allergic context

[PMID:31466978] [PARTIAL] interferon gamma could play a key role. To our knowledge, this is the first case report in which Melkersson-Rosenthal syndrome has been observed concurrently with coeliac disease. --- Explanation: Implicates IFN-γ as a central mediator linking MRS to autoimmune and allergic pathways


HGNC.SYMBOL:IL-12/IL-23 signaling pathway

[PMID:32782477] [SUPPORT] IL-12 and IL-23 are linked to the production of IFN-γ, a pivotal mediator of inflammation in peripheral tissues, including orofacial mucosa, by promoting multiple proinflammatory cytokines. --- Explanation: Establishes IL-12/23 signaling as a central pathway driving IFN-γ production and orofacial granulomatous inflammation


HGNC.SYMBOL:SCN1A variants in rare phenotypes

[PMID:37510386] [PARTIAL] MRS is a disorder with variable expressivity and clinical as well as genetic heterogeneity; however, the causative gene remains to be identified... We identified a c.3521C>G missense heterozygous variant in SCN1A carried only by the affected sister. --- Explanation: Documents rare SCN1A variant association in an MRS patient with facial palsy and migraine, suggesting genetic heterogeneity in MRS pathogenesis


MONDO:0007972

[PMID:27083887] [SUPPORT] episodic attacks of vertigo, fluctuating hearing loss, tinnitus, aural pressure --- Explanation: Confirms vertigo as cardinal episodic manifestation of MD

[PMID:22053211] [SUPPORT] episodes of vertigo associated with hearing loss and tinnitus --- Explanation: Large epidemiological study documents episodes of vertigo as defining MD feature


MONDO:0007972

[PMID:27083887] [SUPPORT] episodic attacks of vertigo, fluctuating hearing loss, tinnitus, aural pressure --- Explanation: Establishes fluctuating sensorineural hearing loss as core MD feature

[PMID:22053211] [SUPPORT] MD, an inner ear disorder characterized by episodes of vertigo associated with hearing loss and tinnitus --- Explanation: Confirms hearing loss as cardinal MD manifestation in large epidemiological study


MONDO:0007972

[PMID:27083887] [SUPPORT] episodic attacks of vertigo, fluctuating hearing loss, tinnitus, aural pressure --- Explanation: Confirms tinnitus as defining component of MD clinical tetrad

[PMID:22053211] [SUPPORT] episodes of vertigo associated with hearing loss and tinnitus --- Explanation: Epidemiological evidence reaffirms tinnitus as hallmark MD symptom


MONDO:0007972

[PMID:27083887] [SUPPORT] episodic attacks of vertigo, fluctuating hearing loss, tinnitus, aural pressure --- Explanation: Documents aural pressure/fullness as diagnostic feature of MD clinical presentation


MONDO:0007972


MONDO:0007972

[PMID:29436285] [INDIRECT EVIDENCE] [SUPPORT] on ELS epithelium. AQP2 expression density was significantly elevated in MD --- Explanation: Immunohistochemical study identifies AQP2 upregulation as a key molecular abnormality in MD endolymphatic sac


MONDO:0007972

[PMID:35280304] [INDIRECT EVIDENCE] [SUPPORT] Up-regulated expression of interferon-γ, interleukin-6 and tumor necrosis factor-α in the endolymphatic sac. --- Explanation: Study documents elevated pro-inflammatory cytokines (IFN-γ, IL-6, TNF-α) in MD endolymphatic sac tissue

[PMID:29326686] [INDIRECT EVIDENCE] [SUPPORT] Carriers of the risk genotype may develop an NF-κB-mediated inflammatory response in MD. --- Explanation: Demonstrates TWEAK-FN14-NF-κB pathway activation as key inflammatory mechanism in MD

[PMID:22053211] [INDIRECT EVIDENCE] [SUPPORT] MD displays an elevated prevalence of systemic AD such as RA, SLE and AS. --- Explanation: Large case-control study establishes association between MD and systemic autoimmune disease

[PMID:21208440] [INDIRECT EVIDENCE] [SUPPORT] Polymorphisms of CD16A and CD32 Fcγ receptors and circulating immune complexes in Ménière's disease. --- Explanation: Case-control study identifies Fcγ receptor polymorphisms and immune complex dysregulation in MD


MONDO:0007972

[PMID:28325925] [INDIRECT EVIDENCE] [SUPPORT] Meniere's disease specimens revealed differential ultrastructural pathological changes in the cellular elements of the microvasculature. --- Explanation: Ultrastructural study documents pathological BLB changes including endothelial and pericyte damage in MD

[PMID:30233382] [INDIRECT EVIDENCE] [SUPPORT] We proposed that oxidative stress mediated the damage to the vestibular endorgan and the BLB in MD. --- Explanation: Documents oxidative stress as key pathogenic mechanism in MD blood-labyrinth barrier dysfunction


MAXO:0000088

[PMID:15090872] [SUPPORT] Initial management of Ménière's disease can involve a low-salt diet and a diuretic. --- Explanation: Establishes low-sodium diet as first-line initial management approach


MAXO:0000058

[PMID:15090872] [SUPPORT] Initial management of Ménière's disease can involve a low-salt diet and a diuretic. --- Explanation: Establishes diuretics as component of initial management strategy


MAXO:0000058

[PMID:11465871] [SUPPORT] The very common use in Europe of histaminergic agents. --- Explanation: Documents histaminergic agent (betahistine) use as standard therapy in Europe


CHEBI:35677

[PMID:11465871] [INDIRECT EVIDENCE] [SUPPORT] The very common use in Europe of histaminergic agents. --- Explanation: Documents histaminergic agent (betahistine) use as standard therapy in Europe


MAXO:0000058

[PMID:15090872] [SUPPORT] Treatment with intratympanic injection of gentamicin can be beneficial when vertigo persists despite optimal medical management. --- Explanation: Establishes intratympanic gentamicin as second-line therapy for refractory vertigo

[PMID:12590850] [SUPPORT] Transtympanic injection, as a quick, easy, well-tolerated, ambulatory and cost-effective technique. --- Explanation: Confirms intratympanic approach as practical, well-tolerated treatment modality


MAXO:0000011


MAXO:0000004


MONDO:0016642

[PMID:40645150] [SUPPORT] new-onset seizures were reported by 26% of newly diagnosed meningioma patients. --- Explanation: Meta-analysis quantifies seizure presentation at diagnosis.


MONDO:0016642

[PMID:40178655] [SUPPORT] Common and non-specific symptoms such as headache and dizziness may be wrongfully attributed to meningiomas, which can lead to unnecessary surgery and anxiety for the patient. --- Explanation: Supports headache as a frequent, non-specific symptom context in incidental meningioma evaluation.


MONDO:0016642

[PMID:40924320] [INDIRECT EVIDENCE] [SUPPORT] Single-cell RNA sequencing revealed a correlation with CD36, a key fatty acid transporter. --- Explanation: Supports CD36-linked fatty acid substrate routing in NOTCH3-associated states.

[PMID:40924320] [INDIRECT EVIDENCE] [SUPPORT] NOTCH3 ICD overexpression (OE) exhibited depletion of fatty acid pools, alongside transcriptional upregulation of canonical FAO genes. --- Explanation: Supports enhanced FAO transcriptional programming under NOTCH3 activation.


MONDO:0016642


MONDO:0016642

[PMID:40924320] [INDIRECT EVIDENCE] [SUPPORT] Additionally, NOTCH3 OE cells exhibit increased resistance to RSL3-induced ferroptosis, a phenotype that was reversed with CPT1 inhibition. --- Explanation: The abstract reports ferroptosis resistance and partial reversibility with metabolic inhibition.


MAXO:0000004

[PMID:34181733] [SUPPORT] A gross total surgical resection including the involved dura is often curative. --- Explanation: EANO guideline supports gross total resection as a key curative-intent approach.


MAXO:0000950

[PMID:34181733] [SUPPORT] a significant proportion of meningiomas, notably in patients that are asymptomatic or elderly or both, may be managed by a watch-and-scan strategy. --- Explanation: Guideline-endorsed conservative management option for selected patients.


MAXO:0009088

[PMID:40802120] [SUPPORT] Our data suggest that SRS is a relatively safe and effective treatment option for recurrent or residual high-grade meningioma, with an acceptable complication profile, even when performed repeatedly. --- Explanation: Human cohort data support repeated radiosurgery as a practical salvage option.


MAXO:0000014

[PMID:34181733] [SUPPORT] Inoperable or recurrent tumors requiring treatment can be treated with radiosurgery, if the size or the vicinity of critical structures allows that, or with fractionated radiotherapy (RT). --- Explanation: EANO guidance supports fractionated RT as a standard local modality in selected cases.


MAXO:0000016

[PMID:40802116] [SUPPORT] Systemic ACT results in significantly increased survival in vivo in high-grade meningioma. --- Explanation: In vivo preclinical data support NY-ESO-1-directed ACT as a candidate strategy.


hgnc:7883

[PMID:40924320] [SUPPORT] While prior work has linked NOTCH3 expression to higher-grade meningiomas and treatment resistance, the metabolic phenotype of NOTCH3 activation remains unexplored in meningioma. --- Explanation: Supports NOTCH3 as an aggressive-disease-associated molecular feature.


hgnc:1663

[PMID:40924320] [SUPPORT] Single-cell RNA sequencing revealed a correlation with CD36, a key fatty acid transporter. --- Explanation: Supports CD36 as a linked metabolic mediator in aggressive meningioma cells.


hgnc:2491

[PMID:40802116] [SUPPORT] NY-ESO-1 expression correlated with tumor grade (n = 35; p < 0.01). --- Explanation: Supports grade-associated CTAG1B/NY-ESO-1 biology in malignant meningioma.


MONDO:0016642

[PMID:40802120] [SUPPORT] All patients had undergone craniotomy and histopathologic confirmation of atypical or anaplastic meningioma. --- Explanation: Confirms grade II/III pathology as a defining tissue-level feature in the studied cohort.


MONDO:0016642

[PMID:40802120] [SUPPORT] Atypical meningioma accounted for the vast majority of cases (105; 93.8%) with only 7 cases of anaplastic meningioma (6.2%). --- Explanation: Quantifies the high-grade histology distribution in a treated clinical cohort.


MONDO:0016642

[PMID:40802116] [SUPPORT] High NY-ESO-1 nuclear expression predicted a worse progression-free-survival (p = 0.0167). --- Explanation: Supports NY-ESO-1 expression as a prognostic molecular feature.


MONDO:0010651

[PMID:25281031] [SUPPORT] Untreated affected individuals suffer failure to thrive and neurodevelopmental delays that usually commence at 6-8 weeks of age. --- Explanation: Documents the characteristic early-onset neurodevelopmental delay of untreated Menkes disease.


MONDO:0010651

[PMID:32714836] [SUPPORT] At birth, affected Menkes infants appear healthy and typically develop normally for 6 to 10 weeks before seizures, failure to thrive, irreversible brain atrophy, and stalled neurodevelopment ensue. --- Explanation: Identifies seizures as a characteristic early neurologic manifestation.


MONDO:0010651

[PMID:22695177] [SUPPORT] Despite this very early intervention with copper, the infant showed hypotonia, developmental delay, and electroencephalographic abnormalities and died of respiratory failure at 5.5 months of age. --- Explanation: Documents hypotonia as a characteristic neurologic manifestation in severe Menkes disease.


MONDO:0010651

[PMID:25281031] [SUPPORT] Untreated affected individuals suffer failure to thrive and neurodevelopmental delays that usually commence at 6-8 weeks of age. --- Explanation: Supports failure to thrive as a core early manifestation of untreated Menkes disease.


MONDO:0010651

[PMID:19888294] [SUPPORT] Progressive neurodegeneration and connective tissue disturbances, together with the peculiar 'kinky' hair are the main manifestations. --- Explanation: Supports kinky hair as a hallmark phenotype; pili torti is the best-fit HPO representation.


MONDO:0010651

[PMID:22695177] [SUPPORT] His skin was dry and wrinkled with a post-mature quality, and loose and redundant on the back and trunk. --- Explanation: Directly documents the cutis laxa phenotype with loose, redundant, wrinkled skin in a Menkes disease patient.


MONDO:0010651

[PMID:32714836] [SUPPORT] At birth, affected Menkes infants appear healthy and typically develop normally for 6 to 10 weeks before seizures, failure to thrive, irreversible brain atrophy, and stalled neurodevelopment ensue. --- Explanation: Documents irreversible brain atrophy as a characteristic feature of untreated Menkes disease.


MONDO:0010651

[PMID:31198482] [SUPPORT] The classic radiographic findings seen in Menke's disease have been documented and include wormian bones, diaphyseal and metaphyseal bone fractures, subdural hematomas, and tortuous intracranial arteries --- Explanation: Documents tortuous intracranial arteries as a classic radiographic finding in Menkes disease.


MONDO:0010651

[PMID:32293788] [SUPPORT] Our prospective results suggest that IJP occurs in approximately 14% (9/66) of Menkes disease patients and appears to be clinically benign with no specific medical or surgical actionability. --- Explanation: Documents the frequency and clinical significance of internal jugular vein phlebectasia in Menkes disease.


MONDO:0010651

[PMID:406641] [SUPPORT] Multiple unusual diverticula of the bladder were observed in 3 of 4 children with Menkes' syndrome. --- Explanation: Documents bladder diverticula as a specific and frequent urological finding in Menkes disease patients.


MONDO:0010651

[PMID:20180106] [SUPPORT] Skeletal findings in infants with Menkes disease, the most characteristic of which are metaphyseal spurs, long-bone fractures and wormian bones, have been widely reported. --- Explanation: Documents wormian bones as one of the most characteristic skeletal findings in Menkes disease.


MONDO:0010651

[PMID:12483361] [SUPPORT] We present a case of Menkes disease complicated by progressive macrocephaly following the development of massive subdural haematomas. --- Explanation: Documents subdural haematomas as a specific complication of Menkes disease that can mimic non-accidental injury.


MONDO:0010651

[PMID:29675083] [SUPPORT] These patients can present with failure to thrive, severe psychomotor retardation, seizures and hypopigmented hair, which is characteristic of this condition. --- Explanation: Documents hypopigmented hair as a characteristic clinical feature of Menkes disease.


MONDO:0010651

[PMID:19888294] [INDIRECT EVIDENCE] [SUPPORT] ATP7A is an energy dependent transmembrane protein, which is involved in the delivery of copper to the secreted copper enzymes and in the export of surplus copper from cells. --- Explanation: Supports ATP7A as the central mediator of intracellular copper delivery and cellular copper efflux.

[PMID:27226607] [INDIRECT EVIDENCE] [SUPPORT] In cells, ATP7A inactivation disrupts copper transport from the cytosol into the secretory pathway. --- Explanation: Demonstrates that ATP7A loss directly disrupts secretory-pathway copper trafficking.


MONDO:0010651


MONDO:0010651

[PMID:18256395] [INDIRECT EVIDENCE] [SUPPORT] Exploiting the deficiency of a copper enzyme, dopamine-beta-hydroxylase, we prospectively evaluated the diagnostic usefulness of plasma neurochemical levels, assessed the clinical effect of early detection, and investigated the molecular bases for treatment outcomes. --- Explanation: Supports dopamine-beta-hydroxylase deficiency as a measurable biochemical consequence of Menkes disease.

[PMID:27226607] [INDIRECT EVIDENCE] [SUPPORT] Thus, ATP7A activity protects mitochondria from excessive copper entry, which is deleterious to redox buffers. --- Explanation: Supports mitochondrial dysfunction and redox imbalance as downstream consequences of ATP7A loss.

[PMID:32714836] [INDIRECT EVIDENCE] [SUPPORT] At birth, affected Menkes infants appear healthy and typically develop normally for 6 to 10 weeks before seizures, failure to thrive, irreversible brain atrophy, and stalled neurodevelopment ensue. --- Explanation: Connects early copper-handling defects to the characteristic neurologic decline and brain atrophy seen in infants.


MONDO:0010651

[PMID:27226607] [INDIRECT EVIDENCE] [SUPPORT] Redox misbalance does not significantly affect mitochondrion morphology or the activity of respiratory complex IV but markedly increases cell sensitivity to even mild glutathione depletion, resulting in loss of cell viability. --- Explanation: Demonstrates that ATP7A loss causes mitochondrial redox imbalance and increased sensitivity to glutathione depletion.

[PMID:27226607] [INDIRECT EVIDENCE] [SUPPORT] Mitochondrial redox misbalance could significantly contribute to pathologies associated with ATP7A inactivation in tissues with paradoxical accumulation of copper (i.e. renal epithelia). --- Explanation: Identifies renal epithelia as a key tissue where mitochondrial redox imbalance contributes to Menkes pathology.


MONDO:0010651

[PMID:32293788] [INDIRECT EVIDENCE] [SUPPORT] This feature and other connective tissue abnormalities appear to be consequences of deficient activity of lysyl oxidase, a copper-dependent enzyme. --- Explanation: Directly links connective-tissue manifestations in Menkes disease to lysyl oxidase deficiency.


MAXO:0000058

[PMID:18256395] [SUPPORT] Among 12 newborns with positive screening tests who were treated early with copper, survival at a median follow-up of 4.6 years was 92%, as compared with 13% at a median follow-up of 1.8 years for a historical control group of 15 late-diagnosis and late-treatment patients. --- Explanation: Supports markedly improved survival with early copper treatment relative to late-treated historical controls.

[PMID:25281031] [SUPPORT] We conclude that early copper histidine for Menkes disease is safe and efficacious, with treatment outcomes influenced by the timing of intervention, and ATP7A mutation. --- Explanation: Confirms safety and efficacy of early copper histidine treatment and emphasizes the importance of presymptomatic treatment.


MAXO:0000058

[PMID:18256395] [INDIRECT EVIDENCE] [SUPPORT] Among 12 newborns with positive screening tests who were treated early with copper, survival at a median follow-up of 4.6 years was 92%, as compared with 13% at a median follow-up of 1.8 years for a historical control group of 15 late-diagnosis and late-treatment patients. --- Explanation: Supports markedly improved survival with early copper treatment relative to late-treated historical controls.

[PMID:25281031] [INDIRECT EVIDENCE] [SUPPORT] We conclude that early copper histidine for Menkes disease is safe and efficacious, with treatment outcomes influenced by the timing of intervention, and ATP7A mutation. --- Explanation: Confirms safety and efficacy of early copper histidine treatment and emphasizes the importance of presymptomatic treatment.


MAXO:0000058


MAXO:0001001

[PMID:30090842] [SUPPORT] Based on these findings, and the absence of a large animal model, we propose cerebrospinal fluid-directed rAAV9-rsATP7A gene therapy plus subcutaneous copper histidinate as a potential therapeutic approach to cure or ameliorate Menkes disease. --- Explanation: Supports ATP7A gene therapy as an experimental mechanistically targeted treatment emerging from mouse-model rescue studies.


hgnc:869

[PMID:18256395] [SUPPORT] Menkes disease is a fatal neurodegenerative disorder of infancy caused by diverse mutations in a copper-transport gene, ATP7A. --- Explanation: Identifies ATP7A as the causal disease gene in Menkes disease.


MONDO:0019210


NCIT:C116870


NCIT:C106432


MAXO:0000004


MAXO:0000014


MAXO:0000647


HGNC.SYMBOL:MCPyV T Antigens


HGNC.SYMBOL:RB1


HGNC.SYMBOL:TP53


NCBITaxon:493803

[PMID:41232971] [SUPPORT] Two subtypes have been identified: Merkel polyomavirus-related (MCPyV), present in 80% of cases in Europe, and UV-related. --- Explanation: Supports the high prevalence of MCPyV-positive Merkel cell carcinoma.


MONDO:0019210

[PMID:41232971] [SUPPORT] Merkel's carcinoma is a rare but highly aggressive cutaneous neuroendocrine --- Explanation: Abstract describes Merkel carcinoma as a highly aggressive cutaneous neuroendocrine tumor.


MONDO:0018868

[PMID:40577679] [SUPPORT] MLD is characterized by demyelination and neurodegeneration of the central and peripheral nervous system, manifesting as progressive motor and cognitive defects in affected individuals. --- Explanation: This review directly identifies progressive cognitive defects as a major clinical manifestation of MLD.


MONDO:0018868

[PMID:30828547] [SUPPORT] The typical clinical course of patients with the late infantile form includes a regression in motor skills with progression to dysphagia, seizures, hypotonia and death. --- Explanation: This abstract directly supports developmental regression through loss of motor skills in late-infantile MLD.


MONDO:0018868

[PMID:30828547] [SUPPORT] The typical clinical course of patients with the late infantile form includes a regression in motor skills with progression to dysphagia, seizures, hypotonia and death. --- Explanation: This abstract directly lists dysphagia in the progression of late-infantile MLD.


MONDO:0018868

[PMID:30828547] [SUPPORT] The typical clinical course of patients with the late infantile form includes a regression in motor skills with progression to dysphagia, seizures, hypotonia and death. --- Explanation: This abstract directly identifies seizures as part of the late-infantile MLD course.


MONDO:0018868

[PMID:30828547] [SUPPORT] The typical clinical course of patients with the late infantile form includes a regression in motor skills with progression to dysphagia, seizures, hypotonia and death. --- Explanation: This abstract directly lists hypotonia in the typical late-infantile MLD course.


MONDO:0018868

[PMID:38564053] [SUPPORT] This case series, however, illustrates the occurrence of severely progressive polyneuropathy shortly after HCT in two patients with late-infantile, one with late-juvenile, and one with adult MLD, leading to the inability to walk or sit without support. --- Explanation: This case series directly supports progressive polyneuropathy as a clinically important phenotype in MLD.


MONDO:0018868

[PMID:40577679] [INDIRECT EVIDENCE] [SUPPORT] Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder caused by disease-causing variants in the gene coding for arylsulfatase A, leading to deficient enzyme activity and subsequent accumulation of sulfatides. --- Explanation: This review directly links ARSA pathogenic variants to deficient enzyme activity in MLD.


MONDO:0018868

[PMID:40577679] [INDIRECT EVIDENCE] [SUPPORT] Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder caused by disease-causing variants in the gene coding for arylsulfatase A, leading to deficient enzyme activity and subsequent accumulation of sulfatides. --- Explanation: This review directly identifies sulfatide accumulation as the key storage abnormality in MLD.


MONDO:0018868

[PMID:40577679] [INDIRECT EVIDENCE] [SUPPORT] MLD is characterized by demyelination and neurodegeneration of the central and peripheral nervous system, manifesting as progressive motor and cognitive defects in affected individuals. --- Explanation: This review identifies CNS demyelination as a central mechanism driving cognitive and motor dysfunction in MLD.


MONDO:0018868


MONDO:0018868

[PMID:38564053] [INDIRECT EVIDENCE] [SUPPORT] This case series, however, illustrates the occurrence of severely progressive polyneuropathy shortly after HCT in two patients with late-infantile, one with late-juvenile, and one with adult MLD, leading to the inability to walk or sit without support. --- Explanation: This case series directly supports progressive polyneuropathy as a major peripheral nervous system manifestation of MLD.


MAXO:0000747

[PMID:40577679] [SUPPORT] Both hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy are most effective when administered before disease onset. --- Explanation: This review directly supports HSCT as a disease-modifying therapy when delivered presymptomatically.


MAXO:0001001

[PMID:35065785] [SUPPORT] Treatment with arsa-cel resulted in sustained, clinically relevant benefits in children with early-onset MLD by preserving cognitive function and motor development in most patients, and slowing demyelination and brain atrophy. --- Explanation: The phase 1/2 and expanded-access study supports arsa-cel as a disease-modifying therapy for early-onset MLD.

[PMID:40577679] [SUPPORT] Research advancements have enabled improved understanding of the effects of allogeneic hematopoietic stem cell transplantation and the development of novel therapeutic approaches, including hematopoietic stem cell gene therapy, which is now authorized in the EU, United Kingdom, and United States as treatment for selected patients with early-onset forms of MLD. --- Explanation: This review confirms regulatory authorization and clinical use of hematopoietic stem cell gene therapy for selected early-onset MLD.


HGNC.SYMBOL:ARSA

[PMID:40577679] [SUPPORT] Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder caused by disease-causing variants in the gene coding for arylsulfatase A, leading to deficient enzyme activity and subsequent accumulation of sulfatides. --- Explanation: This review directly supports ARSA pathogenic variants as the primary genetic cause of MLD and confirms autosomal recessive inheritance.


MONDO:0007983

[PMID:31633898] [SUPPORT] Schmid metaphyseal chondrodysplasia (SMCD) is characterized by progressive short stature that develops by age two years. --- Explanation: GeneReviews confirms progressive short stature as the cardinal growth phenotype.

[PMID:16088909] [SUPPORT] The Schmid type of metaphyseal chondrodyplasia (MCDS) is characterized by short stature, widened growth plates, and bowing of the long bones. --- Explanation: Confirms short stature in a clinical cohort with molecularly confirmed MCDS.


MONDO:0007983

[PMID:31633898] [SUPPORT] The clinical and radiographic features are usually not present at birth, but manifest in early childhood with short limbs, genu varum, and waddling gait. --- Explanation: Lists genu varum as one of the early clinical manifestations.

[PMID:30027601] [SUPPORT] Moderate short stature was a uniform feature associated with predominant involvement of the proximal femora and bow legs resulted in the development of angular deformities. --- Explanation: Confirms genu varum as a uniform feature in a cohort of 12 children.


MONDO:0007983

[PMID:31633898] [SUPPORT] Radiographs show metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping); shortening of the tubular bones; widened growth plates; coxa vara; and anterior cupping, sclerosis, and splaying of the ribs. --- Explanation: Coxa vara listed among the characteristic radiographic findings.

[PMID:30027601] [SUPPORT] A waddling gait was a consequence of coxa vara in eight children. Valgus osteotomy of the proximal femur was planned after physeal closure for the group of children with coxa vara. --- Explanation: Documents coxa vara in 8 of 12 children and its clinical consequence.


MONDO:0007983

[PMID:31633898] [SUPPORT] The clinical and radiographic features are usually not present at birth, but manifest in early childhood with short limbs, genu varum, and waddling gait. --- Explanation: Waddling gait listed as one of the early presenting features.

[PMID:30027601] [SUPPORT] Moderate short stature and a waddling gait associated with pain are the most common clinical presentations. --- Explanation: Confirms waddling gait as one of the most common clinical presentations.


MONDO:0007983

[PMID:16088909] [SUPPORT] The Schmid type of metaphyseal chondrodyplasia (MCDS) is characterized by short stature, widened growth plates, and bowing of the long bones. --- Explanation: Widened growth plates confirmed in molecularly characterized cohort.


MONDO:0007983

[PMID:16088909] [SUPPORT] Radiographs showed metaphyseal changes which were most pronounced at the hips and knees. --- Explanation: Documents metaphyseal irregularity distribution.

[PMID:30027601] [SUPPORT] Diffuse metaphyseal flaring, irregularity, and growth plate widening, which are most severe in the knees, are the most striking radiological features of this disease. --- Explanation: Confirms metaphyseal irregularity as the most striking radiological feature.


MONDO:0007983

[PMID:30027601] [SUPPORT] Diffuse metaphyseal flaring, irregularity, and growth plate widening, which are most severe in the knees, are the most striking radiological features of this disease. --- Explanation: Metaphyseal flaring described as a striking radiological feature.


MONDO:0007983

[PMID:16088909] [SUPPORT] The Schmid type of metaphyseal chondrodyplasia (MCDS) is characterized by short stature, widened growth plates, and bowing of the long bones. --- Explanation: Bowing of the long bones confirmed as a defining feature.


MONDO:0007983

[PMID:31633898] [SUPPORT] Radiographs show metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping); shortening of the tubular bones; widened growth plates; coxa vara; and anterior cupping, sclerosis, and splaying of the ribs. --- Explanation: GeneReviews lists anterior rib cupping as a radiographic finding.


MONDO:0007983

[PMID:31633898] [SUPPORT] Platyspondyly and vertebral end plate irregularities are less common. --- Explanation: GeneReviews notes platyspondyly as a less common but recognized feature.

[PMID:10929364] [SUPPORT] We found that in 9.1% (3/33) of cases reviewed there was definite radiographic evidence of spinal involvement comprising mild platyspondyly, vertebral body abnormalities, and end-plate irregularity. --- Explanation: Documents spinal involvement in 9.1% of a registry cohort, supporting platyspondyly as an uncommon but real component.


MONDO:0007983

[PMID:31633898] [SUPPORT] Joint pain in the knees and hips is common and may limit physical activity. --- Explanation: GeneReviews documents arthralgia as a common clinical feature.


MONDO:0007983

[PMID:31633898] [SUPPORT] Early motor milestones may be delayed due to orthopedic complications. Intelligence is normal. --- Explanation: Motor delay is attributed to orthopedic complications, not neurological involvement.


MONDO:0007983

[PMID:15695517] [INDIRECT EVIDENCE] [SUPPORT] Our data provide the first clear evidence for misfolding of SMCD collagen X mutants, and we propose that solvent exposure of the NC1 thiol may trigger the recognition and degradation of mutant collagen X chains. --- Explanation: First demonstration of collagen X misfolding with MCDS mutations in cell models.

[PMID:15695517] [INDIRECT EVIDENCE] [SUPPORT] In cells expressing mutant collagen X, we detected significantly increased amounts of the spliced form of X-box DNA-binding protein mRNA and up-regulation of BiP, two key markers for the unfolded protein response. --- Explanation: Demonstrates UPR activation with XBP1 splicing and BiP upregulation.

[PMID:19834559] [INDIRECT EVIDENCE] [SUPPORT] Our data demonstrate that triggering ER stress per se in hypertrophic chondrocytes is sufficient to induce the essential features of the cartilage pathology associated with MCDS and confirm that ER stress is a central pathogenic factor in the disease mechanism. --- Explanation: Demonstrates ER stress sufficiency by reproducing MCDS phenotype with unrelated ER stress-inducing protein in hypertrophic chondrocytes.

[PMID:17403716] [INDIRECT EVIDENCE] [SUPPORT] Misfolded FCdel alpha1(X) chains were retained within the endoplasmic reticulum of hypertrophic chondrocytes, activating the unfolded protein response. Our findings provide strong in vivo evidence for a gain-of-function effect that is linked to the activation of endoplasmic reticulum-stress response and altered chondrocyte differentiation, as a possible molecular pathogenesis for MCDS. --- Explanation: In vivo confirmation of ER retention and UPR activation in transgenic mouse model.

[PMID:30543055] [INDIRECT EVIDENCE] [SUPPORT] MANF plays a cytoprotective role in several soft tissues and is upregulated in conditions resulting from intracellular retention of mutant protein, including two skeletal diseases, metaphyseal chondrodysplasia, Schmid type (MCDS) and multiple epiphyseal dysplasia (MED). --- Explanation: MANF upregulation in MCDS reflects a chondroprotective response to ER stress, further supporting ER stress as a central pathogenic axis.

[PMID:29522813] [INDIRECT EVIDENCE] [SUPPORT] disease severity in vivo is increased by ATF6α ablation and decreased by ATF6β ablation. --- Explanation: Demonstrates paradoxical roles of ATF6 paralogs in modulating MCDS severity, with ATF6-alpha protective and ATF6-beta exacerbating.


MONDO:0007983


MONDO:0007983

[PMID:30024379] [INDIRECT EVIDENCE] [SUPPORT] We show the protein kinase RNA-like ER kinase (PERK) pathway that mediates preferential synthesis of ATF4 and CHOP, dominates in causing dysplasia by reverting chondrocyte differentiation via ATF4-directed transactivation of Sox9. --- Explanation: Identifies PERK/ATF4/Sox9 axis as the dominant pathogenic pathway in MCDS.

[PMID:26372225] [INDIRECT EVIDENCE] [SUPPORT] Thus we propose that the pathology of MCDS is underpinned by XBP1 independent UPR-induced dysregulation of C/EBP-β-mediated chondrocyte differentiation. --- Explanation: Demonstrates that MCDS pathology is driven by PERK/CHOP-mediated disruption of C/EBP-beta, independent of IRE1/XBP1.

[PMID:26372225] [INDIRECT EVIDENCE] [SUPPORT] The severity of dwarfism and hypertrophic zone expansion in C/X did not differ significantly from ColXN617K, revealing surprising redundancy for the IRE1/XBP1 UPR pathway in the pathology of MCDS. --- Explanation: XBP1 deletion does not modify MCDS severity, confirming the IRE1/XBP1 pathway is dispensable for pathogenesis.

[PMID:26587667] [INDIRECT EVIDENCE] [SUPPORT] ER stress is triggered in hypertrophic chondrocytes (HCs) in a mouse model (13del) of metaphyseal chondrodysplasia type Schmid (MCDS) caused by misfolded mutant collagen X proteins, but the HCs do not undergo apoptosis; rather chondrocyte differentiation is altered, causing skeletal abnormality. --- Explanation: Proteomics confirms ER-stressed hypertrophic chondrocytes survive rather than undergoing apoptosis, with altered differentiation as the pathogenic outcome.


MONDO:0007983

[PMID:19834559] [INDIRECT EVIDENCE] [SUPPORT] Hypertrophic chondrocyte differentiation and osteoclast recruitment were significantly reduced indicating that the hypertrophic zone was expanded due to a decreased rate of VEGF-mediated vascular invasion of the growth plate. --- Explanation: Demonstrates reduced osteoclast recruitment and VEGF-mediated vascular invasion as a direct consequence of ER stress in hypertrophic chondrocytes.


MONDO:0007983

[PMID:19834559] [INDIRECT EVIDENCE] [SUPPORT] Mice expressing the collagen X mutation had shortened limbs and an expanded hypertrophic zone. --- Explanation: Hypertrophic zone expansion is a hallmark finding in the knock-in mouse model.

[PMID:16088909] [INDIRECT EVIDENCE] [SUPPORT] Our findings suggest that COL10A1 mutations result in a uniform pattern of growth plate abnormalities. --- Explanation: Supports growth plate dysfunction as a uniform consequence of COL10A1 mutations in human patients.


MONDO:0007983

[PMID:15880705] [INDIRECT EVIDENCE] [SUPPORT] Thus for both classes of mutations, functional haploinsufficiency is the most probable cause of the clinical phenotype in SMCD. --- Explanation: Review concluding that haploinsufficiency is the common proximate mechanism regardless of mutation class.

[PMID:17403716] [INDIRECT EVIDENCE] [SUPPORT] We show that nonsense/frame-shift mutations can elicit a gain-of-function effect, affecting chondrocyte differentiation in the growth plate. --- Explanation: Demonstrates that some nonsense/frameshift mutations also exert gain-of-function effects via ER stress, in addition to haploinsufficiency.


MAXO:0000004

[PMID:31633898] [SUPPORT] corrective osteotomy by guided growth surgery or valgus osteotomy may be considered in late childhood / adolescence in those with progressive or symptomatic varus deformity, significant coxa vara, triangular fragment in the interior femoral neck, or poor or deteriorating function --- Explanation: GeneReviews management recommendations for surgical intervention.

[PMID:30027601] [SUPPORT] Osteotomies to correct bow legs are sometimes combined with lengthening procedures. Recurrence of the deformities with growth is not uncommon; therefore, hemiepiphysiodesis or stapling might be indicated in some cases. --- Explanation: Describes orthopedic surgical experience including risk of deformity recurrence.

[PMID:16088909] [SUPPORT] Six patients had lower limb deformities, which necessitated orthopedic surgeries in all of them. --- Explanation: Confirms orthopedic surgery needed in patients with significant deformity.


MAXO:0000011

[PMID:31633898] [SUPPORT] Management of orthopedic complications by an orthopedist, physiotherapist, occupational therapist, and pain specialist as indicated; joint-friendly exercise, weight management; mobility device as needed --- Explanation: GeneReviews management recommendations for supportive care.


MAXO:0000079

[PMID:31633898] [SUPPORT] Once the COL10A1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for SMCD and preimplantation genetic testing are possible. --- Explanation: GeneReviews genetic counseling section.


MAXO:0000058

[PMID:30010889] [SUPPORT] treatment of the mice with carbamazepine (CBZ), a drug which stimulates intracellular proteolysis and alleviates ER stress, effectively reduced the disease severity in this model of MCDS caused by a premature stop codon in the Col10a1 gene. Specifically, the drug reduced ER stress in the growth plate, restored growth plate architecture toward the wild-type state, significantly increased bone growth and within 2 weeks of treatment corrected the MCDS-induced hip distortion. --- Explanation: Preclinical evidence of carbamazepine efficacy in MCDS mouse model.


MAXO:0000058

[PMID:30024379] [SUPPORT] Treatment of mutant mice with a chemical inhibitor of PERK signaling prevents the differentiation defects and ameliorates chondrodysplasia. By preventing aberrant differentiation, titrated inhibition of the ISR emerges as a rationale therapeutic strategy for stress-induced skeletal disorders. --- Explanation: Preclinical evidence of PERK pathway inhibition as a therapeutic approach.


hgnc:2185

[PMID:8220429] [SUPPORT] We have identified a 13 base pair deletion in one type X collagen allele segregating with autosomal dominant Schmid metaphyseal chondrodysplasia in a large Mormon kindred (lod score = 18.2 at theta = 0). --- Explanation: Original identification of COL10A1 as the causal gene.

[PMID:15880705] [SUPPORT] Schmid metaphyseal chondrodysplasia (SMCD) is a dominantly inherited cartilage disorder caused by mutations in the gene for the hypertrophic cartilage extracellular matrix structural protein, collagen X (COL10A1). --- Explanation: Comprehensive review consolidating the causal gene-disease relationship and mutation spectrum.

[PMID:30010889] [SUPPORT] Mutations, mostly in the region of the COL10A1 gene encoding the C-terminal non-collagenous domain, cause the dwarfism metaphyseal chondrodysplasia type Schmid (MCDS). --- Explanation: Background statement from a mouse model study confirming NC1 domain as the primary mutation hotspot.

[PMID:8220429] [SUPPORT] The expression of type X collagen is restricted to hypertrophic chondrocytes in regions undergoing endochondral ossification, such as growth plates. --- Explanation: Establishes the tissue-restricted expression pattern of COL10A1.

[PMID:41454937] [SUPPORT] Genotype-phenotype analysis of 124 cases previously reported and 4 new cases revealed that NC1 domain mutations were associated with an earlier onset of MCDS than non-NC1 mutations (median 12 vs. 72 months, P = 0.0014). Patients carrying a missense mutation in COL10A1 showed significantly lower height Z-scores (- 3.62 ± 1.95 vs. - 1.99 ± 1.28, P = 0.013) at first and more metaphyseal irregularities in the distal radius/ulna than those with truncating mutations (P = 0.019). --- Explanation: Large genotype-phenotype analysis demonstrating NC1 domain mutations associate with earlier onset and missense mutations with more severe short stature.


MONDO:0007983

[PMID:8220429] [SUPPORT] We have identified a 13 base pair deletion in one type X collagen allele segregating with autosomal dominant Schmid metaphyseal chondrodysplasia in a large Mormon kindred (lod score = 18.2 at theta = 0). --- Explanation: Demonstrates autosomal dominant segregation with high LOD score in a large kindred.

[PMID:31633898] [SUPPORT] Approximately half of individuals diagnosed with SMCD have an affected parent (the heterozygous parent almost always exhibits features of the condition; however, considerable intrafamilial phenotypic variability is observed). Approximately half of individuals diagnosed with SMCD have the disorder as the result of a de novo COL10A1 pathogenic variant. --- Explanation: GeneReviews summary of inheritance pattern including de novo rate and variable expressivity.


MONDO:0004989


MONDO:0004989

[PMID:37386445] [INDIRECT EVIDENCE] [PARTIAL] The metastasis of cancer cells from the primary tumor site to other organs in the body, notably the lungs, bones, brain, and liver, is what causes breast cancer to ultimately be fatal. --- Explanation: This supports the central role of distant dissemination and organotropism in lethal breast cancer.


MONDO:0004989

[PMID:37386445] [INDIRECT EVIDENCE] [SUPPORT] The metastasis of cancer cells from the primary tumor site to other organs in the body, notably the lungs, bones, brain, and liver, is what causes breast cancer to ultimately be fatal. --- Explanation: This directly supports the dominant distant sites highlighted in metastatic breast cancer.


MONDO:0004989

[PMID:27349894] [INDIRECT EVIDENCE] [SUPPORT] Intratumoral biomarker heterogeneity may impact breast cancer classification accuracy, with implications for clinical management. --- Explanation: This supports clinically relevant ER/HER2 heterogeneity that can become consequential during metastatic progression.


HGNC.SYMBOL:ESR1


HGNC.SYMBOL:ERBB2 (HER2)


HGNC.SYMBOL:PIK3CA


HGNC.SYMBOL:TP53


MONDO:0005575


MONDO:0005575

[PMID:25632202] [INDIRECT EVIDENCE] [SUPPORT] KRAS and BRAF mutations are associated with inferior survival, independent of MSI status, in Japanese patients with curatively resected CRC. --- Explanation: This supports the clinical importance of KRAS and BRAF signaling even after accounting for MSI status.


MONDO:0005575

[PMID:29201802] [INDIRECT EVIDENCE] [SUPPORT] The liver is the first location of metastatic disease; due to that the main mechanism of dissemination is through the portal system. --- Explanation: This supports the dominant hepatic tropism of metastatic colorectal cancer.


MONDO:0005575

[PMID:29201802] [INDIRECT EVIDENCE] [PARTIAL] Metastasis of the liver from colorectal cancer represents the final stage of a multistep biological process. --- Explanation: This supports a sequential detachment, invasion, and colonization program in metastatic CRC that is consistent with EMT-linked dissemination.


MONDO:0005575

[PMID:41027285] [INDIRECT EVIDENCE] [SUPPORT] MM tumors exhibited suppressed ferroptosis and activation of the TGF-β signaling pathway, while SM tumors displayed inhibited anoikis and activation of the WNT signaling pathway, accompanied by activated angiogenesis. --- Explanation: This directly supports activated angiogenesis as a distinct metastatic CRC program.


MONDO:0005575

[PMID:40530415] [INDIRECT EVIDENCE] [SUPPORT] Within the "seed and soil" paradigm, disrupting both tumor cells and their supportive microenvironment is essential to suppress disease progression. --- Explanation: This explicitly frames colorectal liver metastasis in seed-and-soil terms.


HGNC.SYMBOL:APC


HGNC.SYMBOL:KRAS


HGNC.SYMBOL:BRAF


HGNC.SYMBOL:Mismatch repair deficiency / MSI-high state


MONDO:0004950


MONDO:0004950

[PMID:41710815] [INDIRECT EVIDENCE] [SUPPORT] Loss of E-cadherin expression in advanced tumor stages, higher nodal metastasis, and perineural invasion elucidate the role of E-cadherin as a useful prognostic immunohistochemical marker in gastrointestinal adenocarcinomas. --- Explanation: This supports a direct relationship between E-cadherin loss and invasive metastatic behavior.


MONDO:0004950

[PMID:37271124] [INDIRECT EVIDENCE] [SUPPORT] Microsatellite instability (MSI) is an important prognostic molecular biomarker for gastric cancer (GC). --- Explanation: This supports MSI as a biologically and clinically important gastric cancer state.


HGNC.SYMBOL:CDH1

[PMID:25079317] [SUPPORT] CDH1 somatic mutations were enriched in the genomically stable subtype (37% of cases). --- Explanation: TCGA data demonstrates CDH1 somatic mutations are enriched in the genomically stable (diffuse) subtype of gastric cancer.


HGNC.SYMBOL:ERBB2 (HER2)

[PMID:25079317] [SUPPORT] Focal amplifications targeted oncogenes such as ERBB2, CCNE1, KRAS, MYC, EGFR, CDK6, GATA4, GATA6 and ZNF217. --- Explanation: TCGA data identifies ERBB2 as a recurrent focal amplification target in gastric cancer.


HGNC.SYMBOL:TP53

[PMID:25079317] [SUPPORT] Among the CIN tumours, we observed TP53 mutations in 71% of tumours. --- Explanation: TCGA data shows TP53 mutations are highly prevalent (71%) in the chromosomal instability subtype of gastric cancer.


HGNC.SYMBOL:ARID1A

[PMID:25079317] [SUPPORT] EBV-positive tumours had frequent ARID1A (55%) and BCOR (23%) mutations and only rare TP53 mutations. --- Explanation: TCGA data shows ARID1A mutations are particularly frequent in EBV-positive gastric cancers.


MONDO:0007256


MONDO:0007256

[PMID:41567639] [INDIRECT EVIDENCE] [SUPPORT] HCC typically arises in patients with chronic liver disease, including hepatitis, cirrhosis, and non-alcoholic fatty liver diseases. --- Explanation: This supports the chronic liver disease background that underlies metastatic HCC.


MONDO:0007256

[PMID:29984212] [INDIRECT EVIDENCE] [SUPPORT] The signaling pathways known to be activated in HCC tissue include the Wnt/β-catenin pathway (up to 50% of HCC), the phosphatidylinositol-3-kinase and protein kinase B (PI3K/Akt) pathway (40–60% of HCC), the Myc pathway (30–60%), the Hedgehog pathway (50–60%), and the MET pathway (30–40%). --- Explanation: This supports Wnt/beta-catenin as a major HCC pathway relevant to metastatic behavior.


MONDO:0007256

[PMID:36318440] [INDIRECT EVIDENCE] [SUPPORT] Liver cancer cells potentially experienced multi-steps during PVTT process, including cancer cells leave from cancer nest, migrate in extracellular matrix, invade the vascular barrier, and colonize in the portal vein. --- Explanation: This directly supports the sequential invasion biology underlying portal vein tumor thrombus.


MONDO:0007256

[PMID:19637355] [INDIRECT EVIDENCE] [SUPPORT] Hepatocellular carcinoma (HCC) is a highly vascular tumor, and angiogenesis is believed to play a considerable role in its development and progression. --- Explanation: This directly supports the importance of angiogenesis in advanced and metastatic HCC.


HGNC.SYMBOL:CTNNB1


HGNC.SYMBOL:TERT promoter


HGNC.SYMBOL:TP53


HGNC.SYMBOL:AXIN1


MONDO:0005012


MONDO:0005012

[PMID:40023845] [INDIRECT EVIDENCE] [SUPPORT] Hotspot BRAF, hotspot NRAS, and NF1 loss-of-function mutations are found in approximately 50%, 25%, and 15% of cutaneous melanomas, respectively. --- Explanation: This supports the dominant mutational architecture underlying metastatic melanoma biology.


MONDO:0005012

[PMID:25788491] [INDIRECT EVIDENCE] [SUPPORT] Programmed death ligand-1 (PD-L1) tumor expression represents a mechanism of immune escape for melanoma cells. --- Explanation: This directly supports PD-L1-mediated immune evasion in metastatic melanoma.


MONDO:0005012

[PMID:40609368] [INDIRECT EVIDENCE] [SUPPORT] Melanoma brain metastases (MBM) affect up to 60 % of advanced melanoma cases and are associated with poor prognosis and significant neurologic morbidity. --- Explanation: This supports brain tropism as a defining feature of advanced melanoma.


HGNC.SYMBOL:BRAF


HGNC.SYMBOL:NRAS


HGNC.SYMBOL:NF1


HGNC.SYMBOL:PTEN


MONDO:0005233


MONDO:0005233

[PMID:29989448] [INDIRECT EVIDENCE] [SUPPORT] Activating mutations in the EGFR and rearrangements in the anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) genes have been identified as oncogenic drivers in non-small-cell lung cancer. --- Explanation: This directly supports the major driver pathways relevant to metastatic NSCLC.


MONDO:0005233

[PMID:31627272] [INDIRECT EVIDENCE] [SUPPORT] Aberrant expression of programmed death ligand 1 (PD-L1) on tumor cells impedes antitumor immunity and instigates immune evasion. --- Explanation: This directly supports immune evasion through PD-L1 in NSCLC.


MONDO:0005233

[PMID:26222080] [INDIRECT EVIDENCE] [SUPPORT] These findings substantiate the importance of the "seed and soil" hypothesis and that successful treatment of brain metastases must include targeting of the organ microenvironment. --- Explanation: This supports organ-specific microenvironmental control of NSCLC brain metastasis behavior.


HGNC.SYMBOL:EGFR


HGNC.SYMBOL:ALK


HGNC.SYMBOL:ROS1


HGNC.SYMBOL:STK11/KEAP1


MONDO:0005211


MONDO:0005211

[PMID:27612856] [INDIRECT EVIDENCE] [SUPPORT] Epithelial ovarian cancer (EOC) dissemination is primarily mediated by the shedding of tumor cells from the primary site into ascites where they form multicellular spheroids that rapidly lead to peritoneal carcinomatosis. --- Explanation: This directly supports the dominant transcoelomic mechanism of ovarian cancer metastasis.


MONDO:0005211

[PMID:31904865] [INDIRECT EVIDENCE] [SUPPORT] Mechanistically, OCAMs can induce decreased platinum-sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell-to-cell interactions. --- Explanation: This supports a direct microenvironmental mechanism of platinum resistance in peritoneal metastasis.


MONDO:0005211

[PMID:38174379] [INDIRECT EVIDENCE] [SUPPORT] All PARPis showed significant benefit, with olaparib showing greater benefit in newly diagnosed and PSR OC women. --- Explanation: This supports the clinically important BRCA-associated HRD subset in metastatic ovarian cancer.


HGNC.SYMBOL:TP53


HGNC.SYMBOL:BRCA1


HGNC.SYMBOL:BRCA2


HGNC.SYMBOL:CCNE1


MONDO:0006047


MONDO:0006047

[PMID:35302596] [INDIRECT EVIDENCE] [SUPPORT] KRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). --- Explanation: This directly supports KRAS as the central driver pathway in PDAC.


MONDO:0006047

[PMID:41814069] [INDIRECT EVIDENCE] [SUPPORT] We explore the biological and spatial-temporal evolution of precancerous lesions, such as PanINs and IPMNs, and examine how phenotypic plasticity and overlapping cellular programs-including squamous transdifferentiation, epithelial-to-mesenchymal transition (EMT), and acquisition of mesenchymal features-contribute to early dissemination, treatment resistance, and surgical failure. --- Explanation: This directly supports EMT-linked early dissemination in pancreatic adenocarcinoma.


MONDO:0006047

[PMID:35449152] [INDIRECT EVIDENCE] [SUPPORT] Perineural invasion (PNI) is a pathologic feature of pancreatic cancer and is associated with poor outcomes, metastasis, and recurrence in pancreatic cancer patients. --- Explanation: This supports perineural invasion as a metastasis-associated feature of pancreatic cancer.


HGNC.SYMBOL:KRAS


HGNC.SYMBOL:SMAD4


HGNC.SYMBOL:CDKN2A


MONDO:0008315


MONDO:0008315

[PMID:30535926] [INDIRECT EVIDENCE] [SUPPORT] Oral enzalutamide (Xtandi®), a second generation androgen receptor inhibitor, is indicated for the treatment of castration-resistant prostate cancer (CRPC) in numerous countries worldwide, with specific indications in this patient population varying between individual countries. --- Explanation: This supports the continued importance of AR signaling in metastatic castration-resistant disease.


MONDO:0008315

[PMID:18639279] [INDIRECT EVIDENCE] [SUPPORT] In contrast with metastases caused by other carcinomas such as breast, thyroid, kidney, and lung that destroy bone and are termed “osteolytic,” prostate cancer generally causes a bone-forming or “osteoblastic” response. --- Explanation: This directly supports the osteoblastic bone tropism that distinguishes metastatic prostate cancer.


HGNC.SYMBOL:AR


HGNC.SYMBOL:PTEN


HGNC.SYMBOL:RB1


MONDO:0005086


MONDO:0005086

[PMID:37085424] [INDIRECT EVIDENCE] [SUPPORT] These include somatic gene mutations such as VHL, PBRM1, SETD2, and BAP1; copy number variations; transcriptomic multigene signatures; and specific immune cell populations. --- Explanation: This supports VHL-centered genomic biology in advanced clear cell RCC.


MONDO:0005086

[PMID:41309336] [INDIRECT EVIDENCE] [SUPPORT] Patients with an MPR at nephrectomy had longer PFS and OS. --- Explanation: This supports a clinically meaningful association between immunotherapy-induced pathologic response and survival in mRCC.


HGNC.SYMBOL:VHL


HGNC.SYMBOL:PBRM1


HGNC.SYMBOL:BAP1


HGNC.SYMBOL:SETD2


MONDO:0007986

[PMID:21658220] [SUPPORT] Autosomal dominant brachyolmia, spondylometaphyseal dysplasia Kozlowski type (SMDK) and metatropic dysplasia (MD) are currently considered three distinct skeletal dysplasias with some shared clinical features, including short stature, platyspondyly, and progressive scoliosis. --- Explanation: This supports short stature as a recurrent metatropic dysplasia feature.


MONDO:0007986

[PMID:20425821] [SUPPORT] Metatropic dysplasia is a clinical heterogeneous skeletal dysplasia characterized by short extremities, a short trunk with progressive kyphoscoliosis, and craniofacial abnormalities that include a prominent forehead, midface hypoplasia, and a squared-off jaw. --- Explanation: This directly supports progressive kyphoscoliosis.


MONDO:0007986

[PMID:21658220] [SUPPORT] Autosomal dominant brachyolmia, spondylometaphyseal dysplasia Kozlowski type (SMDK) and metatropic dysplasia (MD) are currently considered three distinct skeletal dysplasias with some shared clinical features, including short stature, platyspondyly, and progressive scoliosis. --- Explanation: This supports platyspondyly as a shared and recurrent feature.


MONDO:0007986

[PMID:20425821] [SUPPORT] Radiographic findings show dumbbell-shaped long bones with widened metaphyses, very flat and dense vertebral bodies, a halberd-shaped pelvis, and brachydactyly with markedly delayed carpal ossification. --- Explanation: This directly supports widened metaphyses on imaging.


MONDO:0007986

[PMID:20425821] [SUPPORT] Radiographic findings show dumbbell-shaped long bones with widened metaphyses, very flat and dense vertebral bodies, a halberd-shaped pelvis, and brachydactyly with markedly delayed carpal ossification. --- Explanation: This directly supports dumbbell-shaped long bones as a hallmark feature.


MONDO:0007986

[PMID:20425821] [SUPPORT] Metatropic dysplasia is a clinical heterogeneous skeletal dysplasia characterized by short extremities, a short trunk with progressive kyphoscoliosis, and craniofacial abnormalities that include a prominent forehead, midface hypoplasia, and a squared-off jaw. --- Explanation: This supports severe appendicular undergrowth/short extremities.


MONDO:0007986

[PMID:20425821] [INDIRECT EVIDENCE] [SUPPORT] Electrophysiological studies demonstrated that the mutations activate the channel, indicating that the mechanism of disease may result from increased calcium in chondrocytes. --- Explanation: This directly links activating TRPV4 mutations to altered calcium handling in chondrocytes.

[PMID:19232556] [INDIRECT EVIDENCE] [SUPPORT] Similar to autosomal-dominant brachyolmia, the mutations altered basal calcium channel activity in vitro. --- Explanation: This provides in vitro functional evidence for TRPV4 channel hyperactivity.


MONDO:0007986


MONDO:0007986

[PMID:20425821] [INDIRECT EVIDENCE] [SUPPORT] Histological studies in two cases of lethal metatropic dysplasia revealed markedly disrupted endochondral ossification, with reduced numbers of hypertrophic chondrocytes and presence of islands of cartilage within the zone of primary mineralization. --- Explanation: This directly supports disrupted growth plate maturation and endochondral ossification.

[PMID:20425821] [INDIRECT EVIDENCE] [SUPPORT] These data suggest that altered chondrocyte differentiation in the growth plate leads to the clinical findings in metatropic dysplasia. --- Explanation: This links altered chondrocyte differentiation to the clinical skeletal phenotype.


MAXO:0000950

[PMID:20425821] [SUPPORT] Complications can include a small chest with some degree of respiratory compromise beginning in the neonatal period, and unrelenting kyphoscoliosis. --- Explanation: This supports the need for ongoing supportive management in severe disease.


hgnc:18083

[PMID:20425821] [SUPPORT] Dominant mutations in the gene encoding TRPV4, a calcium permeable ion channel, were identified all 10 of a series of metatropic dysplasia cases, ranging in severity from mild to perinatal lethal. --- Explanation: This provides direct evidence for TRPV4 as the causative gene across the severity spectrum.

[PMID:19232556] [SUPPORT] The findings demonstrate that mutations in TRPV4 produce a phenotypic spectrum of skeletal dysplasias from the mild autosomal-dominant brachyolmia to SMDK to autosomal-dominant metatropic dysplasia, suggesting that these disorders should be grouped into a new bone dysplasia family. --- Explanation: This places metatropic dysplasia within a TRPV4 skeletal dysplasia spectrum and supports causality.


MONDO:0007986

[PMID:20425821] [SUPPORT] These data demonstrate that the lethal form of the disorder is dominantly inherited and suggest locus homogeneity in the disease. --- Explanation: This directly supports dominant inheritance, including severe lethal forms.

[PMID:19232556] [SUPPORT] In two sporadic cases, heterozygosity for de novo missense mutations in TRPV4 was found. --- Explanation: This supports frequent de novo dominant presentation in sporadic cases.


MONDO:0002012

[PMID:25205257] [SUPPORT] Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia --- Explanation: Directly supports metabolic acidosis as a frequent presenting feature.


MONDO:0002012

[PMID:25205257] [SUPPORT] Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia --- Explanation: Directly supports hyperammonemia during decompensation.


MONDO:0002012