MAXO:0000950

[PMID:20301473] [SUPPORT] Supportive therapy is provided by specialists from multiple disciplines including neurology, physical therapy, occupational therapy, speech therapy, nutrition, feeding, psychology, social work, and clinical genetics. --- Explanation: GeneReviews outlines the multidisciplinary supportive care approach for NPC.


MAXO:0000079

[PMID:20301473] [SUPPORT] Once the NPC-causing pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible. --- Explanation: GeneReviews confirms genetic testing for at-risk relatives is recommended.


hgnc:7897

[PMID:9211849] [SUPPORT] By positional cloning methods, a gene (NPC1) with insertion, deletion, and missense mutations has been identified in NP-C patients. --- Explanation: Landmark paper identifying NPC1 as the causative gene by positional cloning.

[PMID:22572546] [SUPPORT] Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the brain and other tissues. --- Explanation: Patterson guidelines confirm NPC1 accounts for 95% and NPC2 for 5% of cases.


hgnc:7898

[PMID:22572546] [SUPPORT] Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the brain and other tissues. --- Explanation: Patterson guidelines confirm NPC2 accounts for approximately 5% of NPC cases.


MONDO:0018982

[PMID:20301473] [SUPPORT] NPC is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an NPC-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. --- Explanation: GeneReviews confirms autosomal recessive inheritance with standard Mendelian ratios.


MONDO:0017124

[PMID:26437752] [SUPPORT] Noma is an aggressive orofacial gangrenous pathology that damages hard and soft tissues of the mouth and the face. --- Explanation: The abstract describes noma as an orofacial gangrenous pathology.


MONDO:0005233

[PMID:25359349] [SUPPORT] Severe haemoptysis due to nonsmall cell lung cancer (NSCLC) is considered a grim condition... --- Explanation: The study confirms that hemoptysis is a recognized condition associated with non-small cell lung cancer (NSCLC).

[PMID:33563454] [NO_EVIDENCE] There was no associated hemoptysis, hoarseness, epistaxis, or fever on systemic review. --- Explanation: The case report does not support the presence of hemoptysis in the specific instance of NSCLC described.

[PMID:34807953] [NO_EVIDENCE] A positive association was observed between scores of respiratory symptoms and deaths due to COPD and lung cancer. --- Explanation: The study does not specifically focus on hemoptysis as a symptom of NSCLC.


MONDO:0005233

[PMID:35468688] [SUPPORT] One of the reasons patients with Non-Small Cell Lung Cancer are not fit for treatment is cancer cachexia, which is common (upto 75% of patients) in this group. This metabolic syndrome presents clinically as weight loss (muscle +/- fat), decreased physical function (patients less active) and anorexia on a background of systemic inflammation. --- Explanation: The literature indicates that weight loss is a common symptom in Non-Small Cell Lung Cancer patients due to cancer cachexia.

[PMID:35559635] [SUPPORT] Associated symptoms, including hemoptysis or shortness of breath, or systemic symptoms, including anorexia or weight loss, greatly increase the likelihood of having lung cancer. --- Explanation: The literature mentions weight loss as a common systemic symptom associated with lung cancer, supporting its prevalence in Non-Small Cell Lung Cancer.


MONDO:0005233

[PMID:20536932] [SUPPORT] Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone. --- Explanation: The reference states that bone cancer pain is common in patients with advanced lung cancer, including NSCLC, indicating bone metastases.

[PMID:26690845] [SUPPORT] We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer... Bone metastases were evident at diagnosis in 57.5% of patients. --- Explanation: This reference discusses the occurrence of bone metastases in NSCLC patients, which is linked to symptoms like bone pain.


MONDO:0005233

[PMID:38469616] [SUPPORT] Cancer-related fatigue (CRF) stands out as one of the most prevalent subjective adverse reactions experienced by patients following chemotherapy, often resulting in unfavorable symptoms for elderly non-small cell lung cancer (NSCLC) patients during chemotherapy. --- Explanation: The study highlights that cancer-related fatigue is a prevalent adverse reaction in elderly NSCLC patients undergoing chemotherapy.

[PMID:33755621] [SUPPORT] The most common adverse effects of treatment are leukopenia, lymphopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough. --- Explanation: Fatigue is listed as one of the most common adverse effects of treatment for NSCLC.

[PMID:32013812] [SUPPORT] During the early stage, there is no perspicuous sign/symptoms but later many symptoms emerge in the infected individual such as insomnia, headache, pain, loss of appetite, fatigue, coughing etc. --- Explanation: Fatigue is mentioned as a symptom that emerges in individuals with lung cancer, including NSCLC.

[PMID:26990789] [SUPPORT] Toxicities included neutropenia, febrile neutropenia, fatigue, diarrhea, nausea and vomiting, rash, bleeding, hypertension, and hair loss. --- Explanation: Fatigue is listed as one of the common grade III/IV toxicities associated with treatment for metastatic NSCLC.

[PMID:30537755] [SUPPORT] Non-hematological toxicities of >/= grade 2 included anorexia (27.5%) and fatigue (24.6%). --- Explanation: Fatigue is noted as a non-hematological toxicity in NSCLC patients beyond third-line therapy.


MONDO:0005233

[PMID:26690845] [PARTIAL] Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. ... Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. --- Explanation: The reference indicates that bone metastases are common in NSCLC patients, and skeletal-related events are frequent. However, it does not explicitly categorize bone pain as 'occasional.'

[PMID:20536932] [PARTIAL] Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone. --- Explanation: The reference supports that bone pain is common in lung cancer with bone metastases, but it does not specify the frequency as 'occasional.'

[PMID:27988895] [SUPPORT] Bone pain arising due to skeletal metastases is one of the common complications experienced by the majority of patients suffering from prostate, breast and lung cancer at the advanced stage of the disease. --- Explanation: This reference supports the statement that bone pain is a common complication in advanced lung cancer with skeletal metastases, aligning with the note that it may indicate bone metastases.


MONDO:0005233

[PMID:27466520] [NO_EVIDENCE] The most prevalent symptoms were coughing (EORTC score 41.7), dyspnea (33.9), fatigue (31.9), insomnia (30.3) and pain (21.8). --- Explanation: The study lists pain as one of the prevalent symptoms but does not specify chest pain or its frequency.

[PMID:20536932] [NO_EVIDENCE] Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone. --- Explanation: The study discusses bone cancer pain in the context of lung cancer metastasis but does not mention chest pain or its frequency.


MONDO:0005233

[PMID:23857204] [SUPPORT] Recurrent pneumonias often occur in the setting of an airway obstruction and can be the presenting symptom of an undiagnosed malignancy. --- Explanation: The abstract mentions that recurrent pneumonias often occur due to airway obstruction, which can be a symptom of lung cancer.

[PMID:15723108] [SUPPORT] Obstruction of the airway should be initially evaluated with endoscopic procedures. --- Explanation: This reference supports the statement by indicating that airway obstruction, which can be caused by tumors, is a concern in respiratory emergencies in cancer patients.


MONDO:0005233

[PMID:29484515] [PARTIAL] However, brain metastasis sometimes occurs in early stage NSCLC patients without any neurological symptoms. --- Explanation: The reference indicates that brain metastasis can occur in NSCLC patients, often without neurological symptoms. However, it does not specifically mention headache as an occasional symptom.

[PMID:11754303] [NO_EVIDENCE] Paraneoplastic disorders may affect any part of the central or peripheral nervous systems. --- Explanation: The reference discusses paraneoplastic disorders affecting the nervous system but does not specifically mention headache as a symptom of NSCLC.

[PMID:15056056] [PARTIAL] Brain metastases secondary to primary non-small cell and small cell lung cancer have become an important area of research. --- Explanation: The reference discusses brain metastases in NSCLC but does not specifically mention headache as an occasional symptom.


MONDO:0005233

[PMID:22987962] [INDIRECT EVIDENCE] [SUPPORT] Mutations in EGFR best illustrate the therapeutic relevance of molecular classification. This article reviews the scope of presently known driving molecular alterations, including ROS1, BRAF, KRAS, HER2 and PIK3CA, with a special emphasis on aLK rearrangements, and outlines their potential therapeutic applications. --- Explanation: This reference confirms that mutations in genes such as EGFR, ALK, ROS1, and BRAF are recognized as driving molecular alterations that underpin the malignant phenotype of non-small cell lung cancer.

[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: The reference supports that mutations in EGFR, ALK, and ROS1 genes serve as oncogenic drivers in non-small cell lung cancer, contributing to uncontrolled cell growth and survival.

[PMID:35709927] [INDIRECT EVIDENCE] [SUPPORT] The aim of the current study is to extract meaningful information from the online somatic mutation data (retrieved from cBioPortal) of 16 most significantly mutated oncogenes in non-small-cell lung cancer (NSCLC), namely EGFR, NRAS, KRAS, HER2 (ERBB2), RET, MET, ROS1, FGFR1, BRAF ... for improving our understanding of the pathobiology of the lung cancer. --- Explanation: This reference further lists EGFR, ALK, ROS1, and BRAF among the significantly mutated oncogenes in non-small cell lung cancer, thus supporting the statement.

[PMID:31627700] [INDIRECT EVIDENCE] [SUPPORT] Epidermal growth factor receptor (EGFR) mutations play an important role in the pathogenesis of non-small cell lung cancer. ... In patients with EGFR mutations, a significant improvement in therapeutic outcomes was achieved with the administration of targeted therapy using tyrosine kinase inhibitors. --- Explanation: This reference confirms the crucial role of EGFR mutations in NSCLC pathogenesis, indicating their role in driving tumor growth and survival.

[PMID:33435440] [INDIRECT EVIDENCE] [SUPPORT] Testing the presence of driver mutations in specific genes in lung tumors has thus radically changed the clinical management and outcomes of the disease. ... namely EGFR, KRAS, BRAF, MET, and HER2 mutations or amplification, as well as ALK and ROS1 fusions. --- Explanation: This reference supports that identifying driver mutations in genes like EGFR, ALK, ROS1, and BRAF is crucial in the clinical management of NSCLC, implying their role in uncontrolled cell growth and survival.


MONDO:0005233


MONDO:0005233

[PMID:27416962] [INDIRECT EVIDENCE] [SUPPORT] We are also beginning to understand the methods of immune evasion employed by NSCLC which likely contribute to the 20% response rate to immunotherapy. --- Explanation: The study indicates that non-small cell lung cancer (NSCLC) employs methods of immune evasion, which aligns with the statement.

[PMID:29107330] [INDIRECT EVIDENCE] [SUPPORT] Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. ... Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. --- Explanation: The study describes immune evasion mechanisms such as HLA loss in NSCLC, supporting the statement.

[PMID:37130455] [INDIRECT EVIDENCE] [SUPPORT] Since MHC-I antigen presentation is not essential for cell growth or survival, many cancers inactivate this pathway, and thereby escape control by CD8 T cells. Such immune evasion allows cancers to progress and also become resistant to CD8 T-cell-based immunotherapies, such as checkpoint blockade. --- Explanation: The study discusses how NSCLC cells evade the immune system by inactivating MHC-I antigen presentation, supporting the statement.

[PMID:34484217] [INDIRECT EVIDENCE] [SUPPORT] These data raise the possibility that proteins with mechanical barrier function in NSCLC may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction, which can otherwise be targeted effectively with immunotherapy or collagen therapy. --- Explanation: The study mentions mechanisms employed by NSCLC cells to evade immune destruction, supporting the statement.

[PMID:37086716] [INDIRECT EVIDENCE] [SUPPORT] These data demonstrate that enhanced TRM-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes. --- Explanation: The study outlines mechanisms of immune evasion in NSCLC, such as the loss of MHC class I protein expression, supporting the statement.


MAXO:0000004

[PMID:11720753] [SUPPORT] Surgical resection remains the treatment of choice for early stage non-small cell lung cancer (NSCLC). In stages IA, IB, IIA, IIB and selected stages IIIA surgical treatment offers the best long-term prognosis when a complete resection can be performed. Standard operations include lobectomy, bilobectomy and pneumonectomy. --- Explanation: This indicates that lobectomy and pneumonectomy are standard surgical treatments for localized non-small cell lung cancer.

[PMID:37625619] [SUPPORT] Lobectomy is the standard treatment for patients with early-stage non-small cell lung cancer (NSCLC). --- Explanation: This further reinforces that lobectomy, a type of surgery, is a standard treatment for localized non-small cell lung cancer.


MAXO:0000647

[PMID:12094333] [SUPPORT] Platinum-based chemotherapy is considered the standard treatment for advanced non-small cell lung cancer (NSCLC). Several phase II trials using cisplatin in combination with new chemotherapeutic agents, such as gemcitabine, the taxanes, vinorelbine, and irinotecan, showed impressive response rates and suggested an improvement in overall survival. --- Explanation: This supports the statement that platinum-based chemotherapy (specifically cisplatin) in combination with other agents is a treatment for NSCLC.

[PMID:1329222] [SUPPORT] ... carboplatin, either alone or in combination, in five separate phase II studies for patients with inoperable non-small cell lung cancer (NSCLC). ... Subsequently, combinations of carboplatin/cisplatin, carboplatin/etoposide, and carboplatin/vinblastine have been evaluated in similar patient groups. --- Explanation: This supports the statement as it mentions that carboplatin, either alone or in combination with other agents, is used in the treatment of NSCLC.

[PMID:26775594] [SUPPORT] Of the 1564 patients who were included in the prospective study, 1520 received either cisplatin (54%) or carboplatin (46%) in combination with pemetrexed, gemcitabine, taxanes or vinorelbine. --- Explanation: The study provides evidence that both cisplatin and carboplatin, in combination with other agents, are used in the treatment of NSCLC.

[PMID:35525024] [SUPPORT] Platinum-based chemotherapy with or without immunotherapy is the mainstay of treatment for advanced stage non-small cell lung cancer (NSCLC) lacking a molecular driver alteration. --- Explanation: The mention of platinum-based chemotherapy (cisplatin or carboplatin) as a primary treatment supports the statement.

[PMID:27166967] [SUPPORT] Predicting the feasibility of platinum-based chemotherapy remains an important issue in elderly (over 70 years) patients with non-small cell lung cancer (NSCLC). --- Explanation: This statement supports the use of platinum-based chemotherapy in the treatment of NSCLC, emphasizing its importance even in elderly patients.


MAXO:0000058

[PMID:34154330] [SUPPORT] The review article presents the current state and development of the treatment with tyrosine kinase inhibitors in advanced non-small cell lung cancer. It focuses on the therapeutic progress of traditionally targeted gene mutations EGFR, ALK and ROS1. --- Explanation: The reference discusses EGFR, ALK, and ROS1 inhibitors as targeted therapies for non-small cell lung cancer.

[PMID:15946581] [SUPPORT] The epidermal growth factor receptor (EGFR) is a promising target in the treatment of advanced stage non-small-cell lung cancer (NSCLC). Currently erlotinib and gefitinib are approved by the US Food and Drug Administration. --- Explanation: The reference discusses erlotinib and gefitinib as EGFR inhibitors used in the treatment of non-small cell lung cancer.

[PMID:22932130] [SUPPORT] Both erlotinib and crizotinib have been shown to be effective and safe for subgroup populations, and now personalized treatment for nonsquamous NSCLC has progressed even further. --- Explanation: The reference confirms the use of erlotinib (EGFR inhibitor) and crizotinib (ALK and ROS1 inhibitor) in targeted therapy for non-small cell lung cancer.

[PMID:25240504] [SUPPORT] The availability of ... the EGFR-tyrosine kinase inhibitors erlotinib, gefitinib, afatinib as well as ... the ALK-inhibitor crizotinib has recently changes the treatment algorithm of advanced non-small cell lung cancer. --- Explanation: The reference mentions the use of EGFR inhibitors (erlotinib, gefitinib) and ALK inhibitor (crizotinib) in treating non-small cell lung cancer.

[PMID:25322323] [SUPPORT] The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. --- Explanation: The reference discusses crizotinib as an ALK and ROS1 inhibitor used in the treatment of non-small cell lung cancer.

[PMID:27491402] [SUPPORT] Currently, EGFR TKIs (e.g.: erlotinib, gefitinib, osimertinib) and ALK inhibitors (crizotinib, ceritinib, alectinib) provided a new face for advanced NSCLC outcomes. --- Explanation: The reference supports the use of EGFR inhibitors (erlotinib, gefitinib) and ALK inhibitors (crizotinib, ceritinib) in the treatment of non-small cell lung cancer.

[PMID:34125313] [SUPPORT] Four FDA-approved drugs have significant activity against ROS1+ NSCLC: crizotinib, ciritinib, lorlatinib, and entrectinib. --- Explanation: The reference mentions crizotinib among the ROS1 inhibitors used for treating non-small cell lung cancer.

[PMID:28089942] [SUPPORT] Nowadays, different EGFR TKIs as afatinib, erlotinib and gefitinib are approved worldwide for the treatment of NSCLC harbouring EGFR mutations, in particular exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations. --- Explanation: The reference discusses the use of EGFR inhibitors (erlotinib, gefitinib) in the treatment of non-small cell lung cancer.


MAXO:0000058

[PMID:28059852] [SUPPORT] In accordance with recent results, US Food and Drug Administration approved a checkpoint inhibitor for first-line treatment of metastatic non-small cell lung cancer whose tumors have high PD-L1 expression, and European Medicines Agency approval is expected in early 2017. --- Explanation: The FDA has approved immune checkpoint inhibitors for first-line treatment of metastatic NSCLC with high PD-L1 expression, supporting the use of immunotherapy (including nivolumab and pembrolizumab) for these patients.

[PMID:26927720] [SUPPORT] Data so far available show some conflicting results, but PD-L1 immunohistochemistry looks likely to be introduced into clinical use for selecting patients for treatment with anti-PD-1 or anti-PD-L1 therapies. --- Explanation: The mention of PD-L1 immunohistochemistry being introduced for clinically selecting patients for anti-PD-1 therapies supports the statement.

[PMID:32189549] [PARTIAL] A subset of patients who were treated beyond progression with ICI achieved a clinically meaningful response with durable disease control. --- Explanation: While it shows the effectiveness of checkpoint inhibitors, it is about treatment beyond progression and does not specifically address high PD-L1 expression.

[PMID:29140105] [PARTIAL] Single-agent durvalumab showed clinical efficacy and a manageable safety profile in advanced non-small-cell lung cancer, particularly the >/=25% PD-L1+ population. --- Explanation: This supports the efficacy of durvalumab particularly in PD-L1+ populations but does not specifically mention nivolumab or pembrolizumab.

[PMID:33306411] [PARTIAL] For the majority of patients, ICIs are cost-effective for lung cancer management. --- Explanation: This supports the efficacy of ICIs but does not specifically address tumors with high PD-L1 expression.


MAXO:0000014

[PMID:7540125] [PARTIAL] recent notable developments have occurred involving radiation therapy (RT) for patients with non-small cell lung cancer (NSCLC)... For palliation of tumor-related symptoms... metastases to the adrenal gland, liver, and subcutaneous tissues can be palliated successfully by brief courses of RT. Intrathoracic tumor symptoms are well palliated by brief courses of thoracic RT. --- Explanation: Supports the use of RT for palliation of symptoms and metastatic sites, but does not specifically mention its use for localized disease.

[PMID:8853542] [PARTIAL] In the palliation of non-small cell lung cancer... in the management of chest disease, bone metastases, and brain metastases. --- Explanation: Supports the use of RT in palliation of symptoms and brain metastases.

[PMID:32140986] [SUPPORT] Concurrent chemoradiation is the cornerstone of treatment of unresectable, locally advanced NSCLC. --- Explanation: Supports the use of RT for locally advanced (localized) disease.

[PMID:30441934] [SUPPORT] Radiotherapy should also be considered for locally advanced disease. --- Explanation: Supports the use of RT for locally advanced (localized) disease.

[PMID:27467543] [SUPPORT] Stereotactic body radiation therapy has been increasingly used to safely deliver LAT and provide high local control in nonoperable non-small-cell lung cancer patients. --- Explanation: Supports the use of RT for localized disease particularly in nonoperable cases.


HGNC.SYMBOL:EGFR

[PMID:23647298] [SUPPORT] EGFR mutations are a relatively frequent event in non-small-cell lung cancer, generally consisting of exon 19 deletion or exon 21 substitution. In adenocarcinoma, additional rare mutations are detectable in the EGFR gene. --- Explanation: The reference indicates that EGFR mutations, including activating mutations, are a frequent event, which matches the statement that such mutations occur occasionally.

[PMID:27926500] [SUPPORT] The results of this study demonstrate that EGFR-TKI therapy results in survival benefits for EGFR-mutant advanced NSCLC patients, regardless of gender, smoking history, pathologic type, type of EGFR mutations, brain metastasis and timing of targeted therapy. --- Explanation: This study further supports the association of EGFR activating mutations in NSCLC and the effectiveness of targeted therapies, implying the commonality and impact of these mutations.

[PMID:32107398] [SUPPORT] EGFR mutation status might be correlated to CT scans imaging phenotypes. --- Explanation: The research recognizes the frequent mutations in EGFR, validating the association stated in the provided statement.

[PMID:30520383] [SUPPORT] Moreover, 10 to 15% of all NSCLCs harbor EGFR (epidermal growth factor receptor) activating mutations. --- Explanation: The frequency (10-15%) explicitly mentioned aligns well with the occasional occurrence stated in the statement.

[PMID:18957054] [SUPPORT] Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer. --- Explanation: The reference confirms that activating mutations in EGFR are significant and frequent enough to impact treatment and response, supporting the statement's claim.

[PMID:32657049] [SUPPORT] We describe the clinical features, genetic profile, and their correlation in NSCLC patients... The frequency of mutations in EGFR, MET, and RET were significantly higher in nonsmokers than in smokers. --- Explanation: By describing EGFR mutations as a notable factor linked with clinical and demographic attributes of NSCLC patients, it supports the occasional frequency mentioned in the statement.

[PMID:23621221] [SUPPORT] Mutations affecting the epidermal growth factor receptor (EGFR) are good predictors of clinical efficacy of EGFR tyrosine kinase inhibitors (TKI) in patients with non-small cell lung cancer. --- Explanation: The study acknowledges the association of EGFR mutations with clinical outcomes in NSCLC, supporting the idea of their occasional prevalence.


HGNC.SYMBOL:ALK

[PMID:30878128] [SUPPORT] The ALK receptor tyrosine kinase (ALK) gene encodes a transmembrane protein rearranged in 2-7% of non-small cell lung cancer (NSCLC) cases. --- Explanation: The literature describes ALK rearrangements occurring in 2-7% of NSCLC cases, supporting the statement that ALK rearrangements are occasional in frequency in NSCLC.

[PMID:35986977] [SUPPORT] the presence of ALK/ROS rearrangements in our study is associated with an approximately threefold to fourfold increase in thrombosis risk in NSCLC patients. --- Explanation: The mention of ALK rearrangements aligns with the statement indicating that they are a recognised genetic association in NSCLC.

[PMID:36806787] [SUPPORT] more commonly recognized alterations (such as KRAS, BRAF, MET and ERBB family mutations, or ALK, RET and ROS1 fusions) --- Explanation: The literature identifies ALK rearrangements as part of more commonly recognized alterations/subtypes in NSCLC, supporting their occasional occurrence.


HGNC.SYMBOL:ROS1

[PMID:35200557] [SUPPORT] ROS-1 rearrangement is found in 0.9-2.6% of non-small-cell lung cancers (NSCLCs), mostly lung adenocarcinomas. --- Explanation: The literature states that ROS-1 rearrangement occurs in a small percentage of NSCLCs, supporting the statement that ROS1 gene rearrangements are occasional in NSCLC.

[PMID:35986977] [SUPPORT] ROS and ALK rearrangement is highly associated with TE development, with HR of 4.04 ... p = 0.005 --- Explanation: The literature mentions ROS1 rearrangements in the context of their association with thromboembolic events, indicating the presence and relevance of these genetic alterations in NSCLC.

[PMID:34325210] [SUPPORT] We investigated the clinical characteristics and gene mutation rate of non-small cell lung cancer patients with osteoblastic bone metastases at the time of the initial diagnosis. ... two were ROS1 rearrangement-positive. --- Explanation: This reference confirms the presence of ROS1 rearrangements in a subgroup of NSCLC patients, which aligns with the statement regarding the occasional frequency of these rearrangements.

[PMID:36806787] [SUPPORT] Less commonly identified alterations (such as...ROS1 fusions). --- Explanation: The literature identifies ROS1 fusions as less common alterations in NSCLC, which supports the occasional occurrence of these gene rearrangements.


HGNC.SYMBOL:KRAS

[PMID:33618059] [SUPPORT] Mutation in the gene that encodes Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic driver in advanced non-small cell lung cancer, occurring in approximately 30% of lung adenocarcinomas. --- Explanation: This reference confirms that KRAS activating mutations are present in non-small cell lung cancer (NSCLC).

[PMID:23723294] [SUPPORT] Although EGFR mutations were most frequent in patients with ADC and never/light smokers from Asia, and KRAS mutations were most frequent in patients with ADC and ever/heavy smokers from Western countries, both were detected outside these subgroups. --- Explanation: This reference supports the occurrence of KRAS mutations in NSCLC, indicating they are within a notable frequency and linked to specific subgroups.

[PMID:31862576] [SUPPORT] KRAS mutations are one of the most prevalent alterations in non-small cell lung cancer. --- Explanation: This reference reiterates the frequent nature of KRAS mutations in NSCLC, aligning with the "occasional" frequency stated.


HGNC.SYMBOL:STK11


HGNC.SYMBOL:KEAP1


HGNC.SYMBOL:TP53


HGNC.SYMBOL:G6PD


ECTO:6000029

[PMID:27188576] [SUPPORT] Non-small-cell lung cancer (NSCLC), a heterogeneous class of tumours, represents approximately 85% of all new lung cancer diagnoses. Tobacco smoking remains the main risk factor for developing this disease. --- Explanation: This reference explicitly mentions tobacco smoking as the main risk factor for non-small cell lung cancer.

[PMID:24976334] [SUPPORT] The never-smokers had a significantly better prognosis than ever-smokers among Ad patients, whereas the light-smokers had a significantly worse prognosis than heavy smokers among Sq patients. --- Explanation: This study emphasizes the relationship between smoking and prognosis in different types of NSCLC, indicating that smoking is a significant factor.

[PMID:9498897] [SUPPORT] Tobacco smoke has been shown to increase the risk of lung cancer down to the lowest exposure levels. Environmental tobacco smoke contains the same carcinogenic compounds as those found in the tobacco smoke inhaled directly by the smoker. --- Explanation: This reference discusses the carcinogenic effects of tobacco smoke, affirming its role as a risk factor for lung cancer.

[PMID:34083039] [SUPPORT] Smoking is a major risk factor for a variety of diseases, including cancer and immune-mediated inflammatory diseases. Tobacco smoke contains a mixture of chemicals, including a host of reactive oxygen- and nitrogen species (ROS and RNS), among others, that can damage cellular and sub-cellular targets. --- Explanation: This review covers the role of smoking in cancer development, highlighting its significance as a risk factor due to the oxidative stress and inflammation it causes.

[PMID:19020892] [SUPPORT] Arsenic exposure was associated with non-small cell lung cancer. Silicosis turned out as major determinant of the cell type related with arsenic. --- Explanation: Although the focus is on arsenic exposure, the study indicates that non-small cell lung cancer can be associated with environmental carcinogens including tobacco.


ECTO:9000097

[PMID:12075673] [PARTIAL] Based on the most recent findings, there is some evidence that radon may contribute to lung cancer risk in current smokers in high residential radon environments... The situation regarding the risk of lung cancer from radon in non-smokers (ex and never) is unclear. --- Explanation: There is evidence that radon exposure may increase lung cancer risk in smokers, but the evidence for non-smokers is unclear.

[PMID:38159450] [SUPPORT] Miners increased risk of contracting lung cancer is included. It is concluded that the mine ventilation system satisfies the conditions required by the current radiological protection of the miners. --- Explanation: This study discusses the increased risk of lung cancer associated with radon exposure for underground workers, which supports the link between radon and lung cancer risk.

[PMID:20429156] [NO_EVIDENCE] Environmental factors in cancer... radon. --- Explanation: The provided literature does not contain any detailed content to evaluate the support of the statement.

[PMID:25351923] [SUPPORT] Human lung cancers are phenotypically more diverse and broadly constitute 2 types... small cell lung cancers and nonsmall cell lung cancers (NSCLCs). ... especially in lung cancers resulting from exposure to environmental carcinogens. --- Explanation: The reference supports the association between environmental agents, including radon, and non-small cell lung cancer.


MONDO:0005233

[PMID:32657049] [SUPPORT] Of 256 patients with NSCLC, 219 were adenocarcinoma --- Explanation: Abstract reports a NSCLC cohort dominated by adenocarcinoma.


MONDO:0011612

[PMID:39206282] [SUPPORT] Patients showed up for admission with a history of seizures (15/20), lethargy (14/20), hypotonia (11/20), apnea (9/20) --- Explanation: Quantifies seizure frequency at 75% in an NKH cohort.


MONDO:0011612

[PMID:39206282] [SUPPORT] Patients showed up for admission with a history of seizures (15/20), lethargy (14/20), hypotonia (11/20), apnea (9/20) --- Explanation: Documents hypotonia in 55% of NKH patients in this cohort.


MONDO:0011612

[PMID:39206282] [SUPPORT] Patients showed up for admission with a history of seizures (15/20), lethargy (14/20), hypotonia (11/20), apnea (9/20) --- Explanation: Lethargy observed in 70% of NKH patients.


MONDO:0011612

[PMID:39206282] [SUPPORT] Patients showed up for admission with a history of seizures (15/20), lethargy (14/20), hypotonia (11/20), apnea (9/20) --- Explanation: Apnea documented in 45% of NKH patients.


MONDO:0011612

[PMID:39206282] [SUPPORT] Among the nine survivors, varying developmental disorders were observed. --- Explanation: Developmental delay documented in NKH survivors.

[PMID:38589924] [SUPPORT] Twelve children, age 6 to 21y, functioned at mild to severe intellectual disability levels. --- Explanation: Confirms intellectual disability across the spectrum in attenuated NKH.


MONDO:0011612

[PMID:38589924] [SUPPORT] Twelve children, age 6 to 21y, functioned at mild to severe intellectual disability levels. --- Explanation: Directly documents intellectual disability levels in attenuated NKH.


MONDO:0011612

[PMID:39206282] [SUPPORT] dysplasia of the corpus callosum (5/14) --- Explanation: Documents corpus callosum dysplasia in 36% of NKH patients with MRI data.


MONDO:0011612

[PMID:39206282] [SUPPORT] white matter abnormalities (3/14) --- Explanation: White matter abnormalities in 21% of NKH patients with MRI.


MONDO:0011612

[PMID:39206282] [SUPPORT] EEG evaluations showed anomalies such as burst suppression (4/8) and hypsarrhythmia and/or epileptic activity (6/8). --- Explanation: Burst suppression documented in 50% of NKH patients with EEG.


MONDO:0011612

[PMID:38589924] [SUPPORT] Maladaptive behaviors with ADHD-like characteristics were present in more than two thirds of children. --- Explanation: Documents high ADHD-like behavior frequency in attenuated NKH.

[PMID:38589924] [SUPPORT] Maladaptive behaviors were significantly related to female sex and to taking dextromethorphan, but no significant relation between plasma glycine levels and behavior was found. --- Explanation: Explores associations with dextromethorphan but not glycine levels.


MONDO:0011612

[PMID:39206282] [SUPPORT] Patients showed up for admission with a history of seizures (15/20), lethargy (14/20), hypotonia (11/20), apnea (9/20) --- Explanation: Apnea in 45% of NKH patients supports neonatal respiratory distress as a frequent feature.


MONDO:0011612


MONDO:0011612

[PMID:39206282] [INDIRECT EVIDENCE] [SUPPORT] Genetic analyses revealed four new variations and GLDC, AMT gene abnormalities in 13 (65%), 7 (35%) case, respectively. --- Explanation: Supports upstream genetic disruption of glycine cleavage system components in NKH.

[PMID:36190515] [INDIRECT EVIDENCE] [PARTIAL] The H-protein encoded by GCSH has a dual role in protein lipoylation required for bioenergetic enzymes including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase, and in the one-carbon metabolism through its involvement in glycine cleavage enzyme system --- Explanation: Provides component-level mechanistic support for GCSH-linked variant NKH and lipoylation coupling.


MONDO:0011612

[PMID:39206282] [INDIRECT EVIDENCE] [SUPPORT] Median values of cerebrospinal fluid (CSF) glycine levels, plasma glycine levels and CSF/plasma glycine ratios were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range, 0.03-0.60) respectively. --- Explanation: Provides quantitative biochemical data on glycine accumulation in NKH patients.

[PMID:38474060] [INDIRECT EVIDENCE] [SUPPORT] The pathophysiology of nonketotic hyperglycinemia (NKH), a rare neuro-metabolic disorder associated with severe brain malformations and life-threatening neurological manifestations, remains incompletely understood. --- Explanation: Confirms NKH as a neuro-metabolic disorder with severe neurological consequences.


MONDO:0011612

[PMID:38474060] [INDIRECT EVIDENCE] [SUPPORT] it underwent a metabolic switch to an altered serine-glycine-one-carbon metabolism with a coordinated cell growth and cell cycle proliferation response. --- Explanation: Demonstrates SGOC metabolic rewiring in GLDC-deficient human iPSC models.


MONDO:0011612

[PMID:39423724] [INDIRECT EVIDENCE] [SUPPORT] The recognition of glycine as an endogenous ligand at the allosteric activation site of the NMDA-type glutamatergic receptor led to the assumption that the excess glycine in nonketotic hyperglycinemia would result in overactivation of these receptors --- Explanation: Describes glycine's role at the NMDA receptor co-agonist site.


MONDO:0011612

[PMID:38474060] [INDIRECT EVIDENCE] [SUPPORT] GLDC-deficient NPCs had shifted towards a more heterogeneous astrocyte lineage with increased expression of the radial glial markers --- Explanation: Demonstrates altered glial differentiation in NKH cell models.

[PMID:36190515] [INDIRECT EVIDENCE] [SUPPORT] The H-protein encoded by GCSH has a dual role in protein lipoylation required for bioenergetic enzymes including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase, and in the one-carbon metabolism through its involvement in glycine cleavage enzyme system --- Explanation: Demonstrates GCSH moonlighting role linking NKH to lipoylation and bioenergetic defects.


MAXO:0000058

[PMID:36471344] [SUPPORT] Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. --- Explanation: Establishes sodium benzoate as standard glycine reduction therapy.

[PMID:36471344] [SUPPORT] Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. --- Explanation: Provides quantitative data on benzoate therapy effectiveness as comparator.


MAXO:0000088

[PMID:36471344] [SUPPORT] Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. --- Explanation: Demonstrates KD effectiveness for glycine reduction.

[PMID:36471344] [SUPPORT] KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. --- Explanation: Supports KD as an effective glycine reduction strategy.


MAXO:0000058

[PMID:39423724] [PARTIAL] Clear clinical evidence of an added therapeutic benefit beyond the use of glycine reduction strategies from use of either dextromethorphan or ketamine in nonketotic hyperglycinemia has not been documented. --- Explanation: Expert reassessment finds no clear evidence of therapeutic benefit.

[PMID:39423724] [PARTIAL] The systematic use of these NMDA-type receptor antagonists in nonketotic hyperglycinemia should be reevaluated, particularly in light of emerging potential adverse effects. --- Explanation: Recommends reevaluation of NMDA antagonist use due to potential adverse effects.

[PMID:38589924] [PARTIAL] Maladaptive behaviors were significantly related to female sex and to taking dextromethorphan, but no significant relation between plasma glycine levels and behavior was found. --- Explanation: Dextromethorphan use associated with maladaptive behaviors in attenuated NKH.


MAXO:0000058

[PMID:39206282] [PARTIAL] Patients showed up for admission with a history of seizures (15/20) --- Explanation: High seizure frequency (75%) supports the need for anticonvulsant therapy, though the snippet does not specify which anticonvulsants are used.


MAXO:0000950


MAXO:0000079

[PMID:40225406] [SUPPORT] These findings highlight the pathogenic nature of a novel synonymous mutation c.1023G > A, expand the genetic spectrum of GLDC and provide crucial guidance for both the patient's clinical management and family's reproductive genetic counseling. --- Explanation: Demonstrates the value of molecular diagnosis for genetic counseling in NKH families.


HGNC.SYMBOL:Glycine cleavage system gene variants


MONDO:0018997

[PMID:41517739] [SUPPORT] A 22-year-old woman presented with typical dysmorphic features of NS, including...hypertelorism... --- Explanation: Supports hypertelorism as part of the characteristic craniofacial phenotype in clinically diagnosed Noonan syndrome.


MONDO:0018997

[PMID:17222357] [SUPPORT] The main facial features of NS are hypertelorism with down-slanting palpebral fissures, ptosis and low-set posteriorly rotated ears with a thickened helix. --- Explanation: Review evidence explicitly identifies down-slanting palpebral fissures as a main facial feature in Noonan syndrome.


MONDO:0018997

[PMID:17222357] [SUPPORT] The main facial features of NS are hypertelorism with down-slanting palpebral fissures, ptosis and low-set posteriorly rotated ears with a thickened helix. --- Explanation: Review evidence explicitly identifies ptosis as a core facial feature in Noonan syndrome.


MONDO:0018997

[PMID:41517739] [SUPPORT] A 22-year-old woman presented with typical dysmorphic features of NS, including...low-set posteriorly rotated ears... --- Explanation: Case-based clinical evidence supports low-set/posteriorly rotated ears as a characteristic facial finding in Noonan syndrome.


MONDO:0018997

[PMID:41517739] [SUPPORT] A 22-year-old woman presented with typical dysmorphic features of NS, including...a broad neck. --- Explanation: Supports cervical dysmorphology in Noonan syndrome and is consistent with common webbed/broad neck clinical descriptions.


MONDO:0018997

[PMID:11992261] [SUPPORT] pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01) --- Explanation: Confirms high prevalence of pulmonary stenosis in Noonan syndrome, especially with PTPN11 mutations.


MONDO:0018997

[PMID:17603483] [SUPPORT] Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general. --- Explanation: RAF1 mutations are strongly associated with HCM.

[PMID:23791108] [SUPPORT] Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. --- Explanation: RIT1 mutations confer high risk of hypertrophic cardiomyopathy.

[PMID:11992261] [SUPPORT] hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P<.005) --- Explanation: PTPN11 mutations are associated with lower HCM risk compared to other NS genes.


MONDO:0018997

[PMID:41718520] [SUPPORT] An infant presented with a large secundum atrial septal defect complicating NS-HCM. --- Explanation: Supports atrial septal defect as a documented structural cardiac manifestation in Noonan syndrome.


MONDO:0018997

[PMID:41577878] [SUPPORT] Short stature is a key NSSD feature. --- Explanation: Large multicenter Noonan-spectrum cohort data support short stature as a prevalent and clinically significant growth phenotype.


MONDO:0018997

[PMID:11992261] [SUPPORT] The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. --- Explanation: Pectus deformity is recognized as a common feature across genotypes.


MONDO:0018997

[PMID:11992261] [SUPPORT] The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. --- Explanation: Cryptorchidism is recognized as a common feature across Noonan syndrome genotypes.


MONDO:0018997

[PMID:24444506] [SUPPORT] Most affected individuals have characteristic facial features that evolve with age; a broad, webbed neck; increased bleeding tendency; and a high incidence of congenital heart disease, failure to thrive, short stature, feeding difficulties, sternal deformity, renal malformation, pubertal delay, cryptorchidism, developmental or behavioral problems, vision problems, hearing loss, and lymphedema. --- Explanation: This clinical review supports bleeding tendency/easy bruising as a common hematologic phenotype in Noonan syndrome.


MONDO:0018997

[PMID:41560462] [SUPPORT] All patients reported somatosensory symptoms consistent with peripheral neuropathy...electrodiagnostic testing was consistent with peroneal neuropathy in one patient. --- Explanation: Supports peripheral neuropathy as a clinically meaningful neurologic manifestation in adults with Noonan-spectrum disorders.


MONDO:0018997

[PMID:24444506] [SUPPORT] Most affected individuals have characteristic facial features that evolve with age; a broad, webbed neck; increased bleeding tendency; and a high incidence of congenital heart disease, failure to thrive, short stature, feeding difficulties, sternal deformity, renal malformation, pubertal delay, cryptorchidism, developmental or behavioral problems, vision problems, hearing loss, and lymphedema. --- Explanation: Supports lymphedema as a recognized clinical manifestation in Noonan syndrome.


MONDO:0018997

[PMID:11992261] [SUPPORT] The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. --- Explanation: Developmental delay is a recognized feature across Noonan syndrome genotypes.


MONDO:0018997

[PMID:20301303] [SUPPORT] Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population. --- Explanation: GeneReviews reports mild intellectual disability in a substantial minority of individuals with Noonan syndrome.


MONDO:0018997

[PMID:17222357] [SUPPORT] Other associated features are webbed neck, chest deformity, mild intellectual deficit, cryptorchidism, poor feeding in infancy, bleeding tendency and lymphatic dysplasias. --- Explanation: Supports poor feeding in infancy as a common early-life manifestation in Noonan syndrome.


MONDO:0018997

[PMID:11992261] [INDIRECT EVIDENCE] [SUPPORT] All defects were missense, and several were recurrent. The vast majority of mutations altered amino acid residues located in or around the interacting surfaces of the N-SH2 and PTP domains --- Explanation: PTPN11 mutations cluster at the N-SH2/PTP interface, disrupting autoinhibition.


MONDO:0018997

[PMID:17143285] [INDIRECT EVIDENCE] [SUPPORT] Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. --- Explanation: SOS1 mutations are gain-of-function, enhancing RAS-GTP loading.


MONDO:0018997

[PMID:17603483] [INDIRECT EVIDENCE] [SUPPORT] Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding. --- Explanation: RAF1 mutations disrupt autoinhibitory 14-3-3 binding.


MONDO:0018997

[PMID:23791108] [INDIRECT EVIDENCE] [SUPPORT] These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes. --- Explanation: RIT1 gain-of-function mutations drive aberrant MAPK signaling.


MONDO:0018997

[PMID:39352760] [INDIRECT EVIDENCE] [SUPPORT] Cardiomyocyte size and the expression of RAS subfamily members, including MRAS and RIT1, were significantly increased in the left ventricles (LVs) of mutant male mice. --- Explanation: Supports LZTR1 loss-of-function effects on RAS-family proteostasis and downstream tissue-level cardiac phenotypes.


MONDO:0018997


MONDO:0018997

[PMID:17143285] [INDIRECT EVIDENCE] [SUPPORT] SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. --- Explanation: Supports ERK cascade hyperactivation as a convergent signaling consequence of NS-associated upstream mutations.


MONDO:0018997

[PMID:11992261] [INDIRECT EVIDENCE] [SUPPORT] pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01) --- Explanation: Demonstrates that pulmonary valve stenosis is highly associated with PTPN11 mutations in Noonan syndrome.


MONDO:0018997

[PMID:17603483] [INDIRECT EVIDENCE] [SUPPORT] Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general. --- Explanation: Demonstrates strong association between RAF1 mutations and HCM, implicating the kinase pathway in cardiac hypertrophy.

[PMID:23791108] [INDIRECT EVIDENCE] [SUPPORT] Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. --- Explanation: RIT1 mutations are strongly associated with hypertrophic cardiomyopathy.


MAXO:0000780

[PMID:41577878] [SUPPORT] GH therapy was associated with an increase in height SDS from -2.92 to -1.97 (median) following 5 years, and to -1.68 in those with final height. --- Explanation: Large multicenter cohort evidence supports growth hormone therapy for short stature in Noonan syndrome spectrum disorders.


MAXO:0000780

[PMID:41577878] [INDIRECT EVIDENCE] [SUPPORT] GH therapy was associated with an increase in height SDS from -2.92 to -1.97 (median) following 5 years, and to -1.68 in those with final height. --- Explanation: Large multicenter cohort evidence supports growth hormone therapy for short stature in Noonan syndrome spectrum disorders.


MAXO:0000004

[PMID:41718520] [SUPPORT] The patient was treated with trametinib to improve cardiac hypertrophy and then underwent successful surgical closure of the atrial septal defect. --- Explanation: Demonstrates feasibility of staged surgical management for structural heart disease in severe Noonan-associated cardiomyopathy.


MAXO:0000004

[PMID:41718520] [INDIRECT EVIDENCE] [SUPPORT] The patient was treated with trametinib to improve cardiac hypertrophy and then underwent successful surgical closure of the atrial septal defect. --- Explanation: Demonstrates feasibility of staged surgical management for structural heart disease in severe Noonan-associated cardiomyopathy.


MAXO:0000004


MAXO:0000058

[PMID:41718520] [SUPPORT] Trametinib, an MEK inhibitor that attenuates abnormal signaling in the RAS/MAPK pathway, has been shown to improve NS-HCM outcomes. --- Explanation: Supports MEK inhibition as a targeted strategy for severe Noonan-associated hypertrophic cardiomyopathy in early clinical use.


MAXO:0000058

[PMID:41718520] [INDIRECT EVIDENCE] [SUPPORT] Trametinib, an MEK inhibitor that attenuates abnormal signaling in the RAS/MAPK pathway, has been shown to improve NS-HCM outcomes. --- Explanation: Supports MEK inhibition as a targeted strategy for severe Noonan-associated hypertrophic cardiomyopathy in early clinical use.


MAXO:0000058


MAXO:0009101

[PMID:20301303] [SUPPORT] Developmental disabilities are addressed by early intervention programs and individualized education strategies. --- Explanation: GeneReviews supports early intervention services as standard management for developmental disability in Noonan syndrome.


MAXO:0009101

[PMID:20301303] [INDIRECT EVIDENCE] [SUPPORT] Developmental disabilities are addressed by early intervention programs and individualized education strategies. --- Explanation: GeneReviews supports early intervention services as standard management for developmental disability in Noonan syndrome.


MAXO:0000930

[PMID:17222357] [SUPPORT] Physiotherapy and/or speech therapy should be offered if indicated. --- Explanation: Supports speech therapy as recommended supportive care in Noonan syndrome management.


MAXO:0000930

[PMID:17222357] [INDIRECT EVIDENCE] [SUPPORT] Physiotherapy and/or speech therapy should be offered if indicated. --- Explanation: Supports speech therapy as recommended supportive care in Noonan syndrome management.


MAXO:0000011

[PMID:17222357] [SUPPORT] Physiotherapy and/or speech therapy should be offered if indicated. --- Explanation: Supports physiotherapy (physical therapy) for motor/developmental support in Noonan syndrome.


MAXO:0000011

[PMID:17222357] [INDIRECT EVIDENCE] [SUPPORT] Physiotherapy and/or speech therapy should be offered if indicated. --- Explanation: Supports physiotherapy (physical therapy) for motor/developmental support in Noonan syndrome.


hgnc:9644

[PMID:11992261] [SUPPORT] Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS. --- Explanation: Confirms PTPN11 mutations account for approximately half of Noonan syndrome cases.


hgnc:11187

[PMID:17143285] [SUPPORT] We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. --- Explanation: SOS1 mutations are a significant cause of PTPN11-negative Noonan syndrome.


hgnc:9829

[PMID:17603483] [SUPPORT] 18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals)...have missense mutations in RAF1 --- Explanation: RAF1 mutations account for approximately 3% of Noonan syndrome.


hgnc:10023

[PMID:23791108] [SUPPORT] we identified a total of nine missense, nonsynonymous mutations in RIT1...in 17 of 180 individuals (9%) with Noonan syndrome --- Explanation: RIT1 mutations account for approximately 9% of cases without mutations in other known genes.


hgnc:6407

[PMID:17143285] [SUPPORT] KRAS mutations account for <5% of cases of Noonan syndrome --- Explanation: KRAS mutations are a rare cause of Noonan syndrome.


hgnc:6742

[PMID:41675685] [SUPPORT] Final diagnoses included 15 individuals with Noonan syndrome...one each in LZTR1, A2ML1, and MRAS... --- Explanation: Supports LZTR1 as a clinically observed Noonan syndrome genotype in contemporary molecular cohorts.


hgnc:7227

[PMID:41675685] [SUPPORT] Final diagnoses included 15 individuals with Noonan syndrome...one each in LZTR1, A2ML1, and MRAS... --- Explanation: Supports MRAS as a rare but clinically confirmed contributor to Noonan syndrome.

[PMID:41517739] [SUPPORT] Whole-exome sequencing identified a heterozygous MRAS c.203C>T (p.Thr68Ile) mutation...supporting the diagnosis of MRAS-associated Noonan syndrome. --- Explanation: Case-level molecular confirmation supports pathogenic MRAS-associated Noonan syndrome with cardiac involvement.


MONDO:0011122


MONDO:0011122

[PMID:14679177] [SUPPORT] Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues. --- Explanation: Defines insulin resistance as a key metabolic phenotype in obesity.

[PMID:27503945] [SUPPORT] Insulin resistance may link accumulation of adipose tissue in obesity to metabolic diseases, although the underlying mechanisms are not completely understood. --- Explanation: Links adipose tissue accumulation in obesity to insulin resistance and metabolic disease.


MONDO:0011122

[PMID:17212793] [INDIRECT EVIDENCE] [SUPPORT] Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss. Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation. --- Explanation: Describes the role of leptin and ghrelin as key hormones regulating energy balance in obesity.

[PMID:17212793] [INDIRECT EVIDENCE] [SUPPORT] In obese subjects the circulating level of the anorexigenic hormone leptin is increased, whereas surprisingly, the level of the orexigenic hormone ghrelin is decreased. It is now established that obese patients are leptin-resistant. --- Explanation: Explains the paradox of elevated leptin levels in obesity with concurrent leptin resistance, contributing to failed energy balance restoration.


MONDO:0011122

[PMID:39456156] [INDIRECT EVIDENCE] [SUPPORT] Under various physiological or pathological conditions, adipose tissue shifts cellular composition, lipid storage, and organelle dynamics to respond to the stress; this remodeling is called "adipose tissue plasticity". --- Explanation: Describes the dynamic remodeling of adipose tissue in response to obesity, including changes in cellular composition and metabolic function.

[PMID:14679177] [INDIRECT EVIDENCE] [SUPPORT] Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells. --- Explanation: Provides histological evidence of macrophage infiltration into dysfunctional adipose tissue in obesity.

[PMID:14679177] [INDIRECT EVIDENCE] [SUPPORT] These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance. --- Explanation: Establishes the causal role of adipose tissue macrophages in obesity-related metabolic dysfunction.


MONDO:0011122

[PMID:14679177] [INDIRECT EVIDENCE] [SUPPORT] Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance. --- Explanation: Establishes both correlative and causative links between chronic inflammation and insulin resistance in obesity.

[PMID:14679177] [INDIRECT EVIDENCE] [SUPPORT] We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue. --- Explanation: Proposes that obesity-induced insulin resistance represents a chronic inflammatory disease originating in adipose tissue.

[PMID:27503945] [INDIRECT EVIDENCE] [SUPPORT] Particularly chronic inflammation in adipose tissue seems to play an important role in the development of obesity-related insulin resistance. --- Explanation: Highlights the central role of chronic adipose tissue inflammation in obesity-related insulin resistance.


MONDO:0011122

[PMID:38490517] [INDIRECT EVIDENCE] [SUPPORT] Leptin acts through its receptor LepRb, expressed mainly in the hypothalamus, and induces a negative energy balance by potent inhibition of feeding and activation of energy expenditure. --- Explanation: Describes the central hypothalamic mechanism by which leptin normally regulates energy balance.

[PMID:38490517] [INDIRECT EVIDENCE] [SUPPORT] However, the majority of patients with obesity presents elevated leptin production, suggesting that in this setting leptin is ineffective in the regulation of energy balance. --- Explanation: Explains leptin resistance in obesity where elevated leptin fails to regulate energy balance through hypothalamic circuits.


MONDO:0011122

[PMID:38286821] [INDIRECT EVIDENCE] [SUPPORT] Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. --- Explanation: Demonstrates that obesity causes mitochondrial fragmentation through RalA in white adipocytes.

[PMID:38286821] [INDIRECT EVIDENCE] [SUPPORT] Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. --- Explanation: Describes the molecular mechanism by which RalA promotes mitochondrial fission through DRP1 dephosphorylation.

[PMID:38286821] [INDIRECT EVIDENCE] [SUPPORT] Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. --- Explanation: Provides human evidence linking DNM1L expression to obesity and insulin resistance.


MAXO:0000088


MAXO:0000058


MAXO:0000004


MAXO:0000077


CHEBI:94686


HGNC.SYMBOL:FTO


HGNC.SYMBOL:MC4R


HGNC.SYMBOL:LEP


HGNC.SYMBOL:LEPR


HGNC.SYMBOL:POMC


MONDO:0007147


MONDO:0007147

[PMID:39595069] [SUPPORT] Emerging clinical evidence suggests that GLP-1RAs and SGLT2 inhibitors can reduce OSA severity and improve daytime sleepiness, potentially reversing the adverse cardiovascular effects observed in OSA. --- Explanation: Confirms that daytime sleepiness is a characteristic symptom of OSA that can be ameliorated with treatment.


MONDO:0007147

[PMID:38672697] [SUPPORT] OSAS significantly impacts quality of life and is associated with increased morbidity and mortality, particularly in the cardiovascular and cognitive domains. --- Explanation: Confirms that cognitive impairment is a major domain of morbidity in OSA.

[PMID:39694586] [SUPPORT] Obstructive sleep apnoea (OSA) contributes to cerebrovascular diseases and cognitive decline. --- Explanation: Establishes the link between OSA and cognitive decline, supported by rodent model evidence of brain injury from intermittent hypoxia.


MONDO:0007147

[PMID:39595069] [SUPPORT] These agents, originally developed for T2D management, have demonstrated pleiotropic effects, including significant weight loss, blood pressure reduction, and amelioration of endothelial dysfunction and arterial stiffness, along with anti-inflammatory benefits, which may be particularly beneficial in OSA. --- Explanation: Indicates that blood pressure elevation is a characteristic feature of OSA requiring therapeutic intervention.

[PMID:38672697] [SUPPORT] OSAS-related complications include cardiovascular disorders, neurological impairments, metabolic dysfunction, and a potential link to cancer. --- Explanation: Confirms that cardiovascular disorders, including hypertension, are a major complication of OSA.


MONDO:0007147

[PMID:38672697] [INDIRECT EVIDENCE] [SUPPORT] BACKGROUND: Obstructive sleep apnea syndrome (OSAS), affecting approximately 1 billion adults globally, is characterized by recurrent airway obstruction during sleep, leading to oxygen desaturation, elevated carbon dioxide levels, and disrupted sleep architecture. --- Explanation: Defines the fundamental pathophysiological mechanism of OSA as recurrent airway obstruction during sleep.

[PMID:36982552] [INDIRECT EVIDENCE] [SUPPORT] Obstructive sleep apnea syndrome (OSAS) is characterized by intermittent hypoxia (IH) during sleep due to recurrent upper airway obstruction. --- Explanation: Confirms that intermittent hypoxia results from recurrent upper airway obstruction, the primary mechanical defect in OSA.


MONDO:0007147

[PMID:38672697] [INDIRECT EVIDENCE] [SUPPORT] The cyclic pattern of intermittent hypoxia in OSAS triggers oxidative stress, contributing to cellular damage. --- Explanation: Directly confirms that intermittent hypoxia in OSA triggers oxidative stress and cellular damage.

[PMID:36982552] [INDIRECT EVIDENCE] [SUPPORT] IH increases oxygen free radicals (ROS) and reduces antioxidant capacities. --- Explanation: Demonstrates the molecular mechanism by which intermittent hypoxia produces oxidative stress through increased ROS and decreased antioxidant defenses.

[PMID:39694586] [INDIRECT EVIDENCE] [SUPPORT] IH-induced oxidative stress (increased malondialdehyde (MDA) and NADPH oxidase (NOX) and decreased superoxide dismutase), increased inflammation (tumour necrosis factor-α, NF-κB and inducible nitric oxide synthase), HIF-1 and apoptosis evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labelling and cleaved caspase-3. --- Explanation: Meta-analysis of rodent models confirming that intermittent hypoxia induces oxidative stress, inflammation, and apoptosis in the brain, establishing causal mechanisms.


MONDO:0007147

[PMID:38672697] [INDIRECT EVIDENCE] [SUPPORT] Obstructive sleep apnea syndrome (OSAS), affecting approximately 1 billion adults globally, is characterized by recurrent airway obstruction during sleep, leading to oxygen desaturation, elevated carbon dioxide levels, and disrupted sleep architecture. --- Explanation: Confirms that disrupted sleep architecture is a fundamental consequence of recurrent airway obstruction in OSA.


MONDO:0007147

[PMID:38672697] [INDIRECT EVIDENCE] [SUPPORT] The review delineates the imbalance between pro-inflammatory and anti-inflammatory factors in OSAS, leading to heightened oxidative stress. --- Explanation: Confirms that OSA is characterized by an imbalance favoring pro-inflammatory factors, resulting in heightened inflammation.

[PMID:36982552] [INDIRECT EVIDENCE] [SUPPORT] OS and metabolic alterations lead OSAS patients to undergo endothelial dysfunction, osteoporosis, systemic inflammation, increased cardiovascular risk, pulmonary remodeling, and neurological alterations. --- Explanation: Demonstrates that systemic inflammation is a key pathophysiological feature of OSA contributing to multiple complications.

[PMID:39694586] [INDIRECT EVIDENCE] [SUPPORT] IH-induced oxidative stress (increased malondialdehyde (MDA) and NADPH oxidase (NOX) and decreased superoxide dismutase), increased inflammation (tumour necrosis factor-α, NF-κB and inducible nitric oxide synthase), HIF-1 and apoptosis evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labelling and cleaved caspase-3. --- Explanation: Meta-analysis evidence showing that intermittent hypoxia induces inflammation through TNF-α and NF-κB activation.


HGNC.SYMBOL:PHOX2B


HGNC.SYMBOL:Craniofacial genes


MONDO:0008111

[PMID:19338053] [SUPPORT] Patients present with a characteristic facial appearance, narrow nose, and hypoplastic alae nasi. --- Explanation: Describes the hallmark craniofacial feature of ODDD.


MONDO:0008111

[PMID:29902798] [SUPPORT] a 14-year-old boy with microphthalmia, microcornea, narrow nasal bridge, hypoplastic alae nasi --- Explanation: Microphthalmia documented as a key clinical feature.


MONDO:0008111


MONDO:0008111

[PMID:29902798] [SUPPORT] hypodontia, dental caries --- Explanation: Dental abnormalities are a core feature of ODDD.


MONDO:0008111

[PMID:12457340] [SUPPORT] This autosomal dominant syndrome presents with craniofacial (ocular, nasal, and dental) and limb dysmorphisms, spastic paraplegia, and neurodegeneration. Syndactyly type III and conductive deafness can occur in some cases --- Explanation: Syndactyly type III is listed as a recognized feature of ODDD.


MONDO:0008111

[PMID:19338053] [SUPPORT] Neurological problems, including dysarthria, neurogenic bladder disturbances, spastic paraparesis, ataxia, anterior tibial muscle weakness, and seizures, are known to occur --- Explanation: Spastic paraparesis is documented among the neurological complications of ODDD.

[PMID:12457340] [SUPPORT] craniofacial (ocular, nasal, and dental) and limb dysmorphisms, spastic paraplegia, and neurodegeneration --- Explanation: Spastic paraplegia listed as a feature of ODDD in the original genetic characterization.


MONDO:0008111

[PMID:19338053] [SUPPORT] Neurological problems, including dysarthria, neurogenic bladder disturbances, spastic paraparesis, ataxia, anterior tibial muscle weakness, and seizures, are known to occur --- Explanation: Seizures listed among the neurological features of ODDD.


MONDO:0008111

[PMID:12457340] [SUPPORT] Syndactyly type III and conductive deafness can occur in some cases, and cardiac abnormalities are observed in rare instances. --- Explanation: Conductive deafness documented as a feature of ODDD.


MONDO:0008111

[PMID:12457340] [INDIRECT EVIDENCE] [SUPPORT] Gap junctions are assemblies of intercellular channels that regulate a variety of physiologic and developmental processes through the exchange of small ions and signaling molecules. --- Explanation: Establishes that gap junctions composed of connexin proteins mediate intercellular signaling critical for development.

[PMID:12457340] [INDIRECT EVIDENCE] [SUPPORT] These mutations may cause misassembly of channels or alter channel conduction properties. --- Explanation: Demonstrates that GJA1 mutations disrupt gap junction function through either channel misassembly or altered conduction.

[PMID:19338053] [INDIRECT EVIDENCE] [SUPPORT] Mutations resulting in ODDD occur in each of the nine domains of the Cx43 protein, and we review our functional experiments and those in the literature, examining the effects of 13 different Cx43 mutations upon gap junction activity. --- Explanation: Confirms mutations across all Cx43 protein domains affect gap junction activity.


MONDO:0008111

[PMID:12457340] [INDIRECT EVIDENCE] [SUPPORT] Expression patterns and phenotypic features of gja1 animal mutants, reported elsewhere, are compatible with the pleiotropic clinical presentation of oculodentodigital dysplasia. --- Explanation: Animal models of gja1 mutations recapitulate the pleiotropic craniofacial and limb phenotypes seen in ODDD.


MONDO:0008111

[PMID:19338053] [INDIRECT EVIDENCE] [SUPPORT] Neurological problems, including dysarthria, neurogenic bladder disturbances, spastic paraparesis, ataxia, anterior tibial muscle weakness, and seizures, are known to occur --- Explanation: Enumerates the neurological manifestations resulting from impaired CNS gap junction function.


MONDO:0008111

[PMID:23606748] [INDIRECT EVIDENCE] [SUPPORT] the trans-dominant effect of R33X together with its complete inability to form a functional channel may explain why patients harboring this autosomal recessive R33X mutant exhibit greater disease burden than patients harboring the R76H mutant. --- Explanation: Functional studies reveal distinct mechanisms for the two known AR mutations, explaining phenotypic severity differences.

[PMID:23606748] [INDIRECT EVIDENCE] [SUPPORT] the R76H mutant trafficked to the plasma membrane to form gap junction-like plaques, whereas the R33X mutant remained diffusely localized throughout the cell, including the nucleus. --- Explanation: The R76H mutant retains some trafficking and channel formation capacity while R33X is completely non-functional.


hgnc:4274

[PMID:19338053] [SUPPORT] we present 28 new cases with 18 novel GJA1 mutations. We include tables summarizing the 62 known GJA1 nucleotide changes leading to Cx43 protein alterations and the phenotypic information available on 177 affected individuals from 54 genotyped families. --- Explanation: Comprehensive summary of 62 GJA1 mutations across 54 families establishes the definitive gene-disease association.

[PMID:12457340] [SUPPORT] We found mutations in the GJA1 gene in all 17 families with oculodentodigital dysplasia that we screened. --- Explanation: The original study found GJA1 mutations in 100% of screened ODDD families.


MONDO:0008111

[PMID:19338053] [SUPPORT] The predominantly autosomal dominant disorder, oculodentodigital dysplasia (ODDD) has high penetrance with intra- and interfamilial phenotypic variability. --- Explanation: Directly states AD inheritance with high penetrance and variable expressivity in ODDD.

[PMID:12457340] [SUPPORT] We found mutations in the GJA1 gene in all 17 families with oculodentodigital dysplasia that we screened. Sixteen different missense mutations and one codon duplication were detected. --- Explanation: Demonstrates the genetic basis of ODDD across multiple families with diverse GJA1 mutations.


MONDO:0008111

[PMID:23606748] [SUPPORT] Surprisingly, there have been two autosomal recessive mutations reported that cause ODDD: a single amino acid substitution (R76H) and a premature truncation mutation (R33X). --- Explanation: Documents two distinct AR mutations causing ODDD by different molecular mechanisms.

[PMID:29902798] [SUPPORT] a novel homozygous mutation (c.442C>T, p.Arg148Ter) was determined in the GJA1 gene leading to a premature stop codon. His phenotypically normal parents were found to be carriers of the same mutation. This is the third family in the literature in which ODDD segregates in an autosomal recessive manner. --- Explanation: Reports a third AR family with a homozygous truncating mutation, confirming recessive inheritance in ODDD.


MONDO:0017136

[PMID:14566439] [SUPPORT] Clinical features are rhizomelic dwarfism with limited extension of elbows and knees and a distinct face with a short nose, depressed nasal bridge, long philtrum, midline haemangiomas in infants and cryptorchidism in males --- Explanation: Rhizomelic dwarfism is described as a cardinal clinical feature across multiple cases.


MONDO:0017136

[PMID:29383834] [SUPPORT] Radiological examination in infancy showed short, broad humeri with relatively narrow distal ends --- Explanation: Confirms short humeri with characteristic distal narrowing as a consistent radiological finding.


MONDO:0017136

[PMID:32655339] [SUPPORT] Both upper and lower limbs are severely affected. These manifestations contrast with normal height and limb shortening restricted to the arms in autosomal dominant omodysplasia (FZD2-related) --- Explanation: Distinguishes the severe four-limb involvement in OMOD1 from the predominantly upper-limb involvement in OMOD2.


MONDO:0017136

[PMID:14566439] [SUPPORT] Radiological findings are distal hypoplasia of the short humerus and femur with characteristic radial dislocation and radioulnar diastasis --- Explanation: Identifies radial dislocation and radioulnar diastasis as characteristic radiological findings.


MONDO:0017136

[PMID:14566439] [SUPPORT] Clinical features are rhizomelic dwarfism with limited extension of elbows and knees --- Explanation: Limited elbow extension is a consistent clinical finding across reported cases.


MONDO:0017136

[PMID:29383834] [SUPPORT] a rare autosomal dominant (AD) skeletal dysplasia characterized by shortened humeri, short first metacarpal, craniofacial dysmorphism --- Explanation: Short first metacarpal is listed as a defining feature of OMOD2.


MONDO:0017136

[PMID:19481194] [SUPPORT] autosomal-recessive omodysplasia, a genetic condition characterized by short-limbed short stature, craniofacial dysmorphism, and variable developmental delay --- Explanation: Short-limbed short stature is described as a defining characteristic of the recessive form.


MONDO:0017136

[PMID:14566439] [SUPPORT] a distinct face with a short nose, depressed nasal bridge, long philtrum --- Explanation: Depressed nasal bridge is listed among the distinct facial features.


MONDO:0017136

[PMID:14566439] [SUPPORT] a distinct face with a short nose, depressed nasal bridge, long philtrum --- Explanation: Long philtrum is a consistent facial feature across reported cases.


MONDO:0017136

[PMID:29383834] [SUPPORT] craniofacial dysmorphism (frontal bossing, depressed nasal bridge, bifid nasal tip, and long philtrum) --- Explanation: Frontal bossing is listed as a craniofacial feature of the dominant form.


MONDO:0017136

[PMID:14566439] [SUPPORT] a distinct face with a short nose, depressed nasal bridge, long philtrum --- Explanation: Short nose is consistently described across omodysplasia cases.


MONDO:0017136

[PMID:14566439] [SUPPORT] midline haemangiomas in infants --- Explanation: Midline hemangiomas in infancy are described as a feature of the recessive form.


MONDO:0017136

[PMID:14566439] [SUPPORT] cryptorchidism in males --- Explanation: Cryptorchidism is described as a feature in males with the recessive form.


MONDO:0017136

[PMID:29383834] [SUPPORT] rhizomelic short stature with elbow restriction, mild facial dysmorphism (depressed broad bridge, short nose, anteverted nostrils, long philtrum, and low-set ears), and genital hypoplasia --- Explanation: Genital hypoplasia is described as a feature of dominant omodysplasia.


MONDO:0017136

[PMID:19481194] [SUPPORT] short-limbed short stature, craniofacial dysmorphism, and variable developmental delay --- Explanation: Variable developmental delay is described in the recessive form.

[PMID:30455931] [SUPPORT] intellectual disability as seen in our patient is not typical --- Explanation: Intellectual disability can occur in dominant omodysplasia but is acknowledged as atypical.


MONDO:0017136

[PMID:19481194] [INDIRECT EVIDENCE] [SUPPORT] All mutations cause truncation of the GPC6 protein and abolish both the HS-binding site and the GPI-bearing membrane-associated domain, and thus loss of function is predicted --- Explanation: Demonstrates that all identified GPC6 mutations are loss-of-function, truncating both the heparan sulfate binding and membrane anchor domains.

[PMID:28696225] [INDIRECT EVIDENCE] [SUPPORT] GPC6-null embryos display most of the abnormalities found in OMOD1 patients and that Hedgehog (Hh) signaling is significantly reduced in the long bones of these embryos --- Explanation: GPC6 knockout mice recapitulate OMOD1 phenotype and demonstrate that reduced Hedgehog signaling in developing long bones is the key pathogenic mechanism.

[PMID:28696225] [INDIRECT EVIDENCE] [SUPPORT] GPC6 stimulates Hh signaling by binding to Hh and Ptc1 at the cilium and increasing the interaction of the receptor and ligand --- Explanation: Establishes the molecular mechanism by which GPC6 promotes Hedgehog signaling at the primary cilium.

[PMID:28869591] [INDIRECT EVIDENCE] [SUPPORT] The results implicate GPC6 as a novel determinant of BMD --- Explanation: Large-scale GWAS identifies GPC6 as a determinant of bone mineral density in the general population, supporting its broader role in skeletal biology beyond omodysplasia.


MONDO:0017136


MONDO:0017136

[PMID:25759469] [INDIRECT EVIDENCE] [SUPPORT] we show reduced ability of this mutant form of FZD2 to interact with its downstream target DISHEVELLED. Furthermore, expressing the mutant form of FZD2 in vitro is not able to facilitate the cellular response to canonical Wnt signaling like wild-type FZD2 --- Explanation: Demonstrates that the FZD2 W548* mutation impairs Dishevelled interaction and canonical Wnt signaling in functional assays.

[PMID:36867021] [INDIRECT EVIDENCE] [SUPPORT] Fzd2em1Smill mutant embryos displayed decreased canonical Wnt signaling in developing limb mesenchyme and disruption of digit chondrocyte elongation and orientation, which is controlled by the β-catenin-independent WNT5A/planar cell polarity (PCP) pathway --- Explanation: Mouse model demonstrates that FZD2 mutations disrupt both canonical and non-canonical Wnt signaling in limb development, directly causing shortened bone elements.

[PMID:36867021] [INDIRECT EVIDENCE] [SUPPORT] FZD2 controls limb development by mediating both canonical and non-canonical Wnt pathways and reveal causality of pathogenic FZD2 mutations in RS and OMOD2 patients --- Explanation: Confirms FZD2 as causative for OMOD2 and shows dual pathway involvement.

[PMID:36967195] [INDIRECT EVIDENCE] [SUPPORT] mutations in each of these signaling components cause Robinow syndrome, a congenital disorder characterized by profound tissue morphogenetic abnormalities --- Explanation: Review establishes that FZD2 is part of the core WNT5A-ROR-FZD-DVL non-canonical signaling module, and that mutations in any component of this pathway cause overlapping Robinow/omodysplasia phenotypes.


MONDO:0017136

[PMID:19481194] [INDIRECT EVIDENCE] [SUPPORT] Expression studies in microdissected mouse growth plate revealed expression of Gpc6 in proliferative chondrocytes --- Explanation: Demonstrates GPC6 expression in the relevant cell type (proliferative growth plate chondrocytes), supporting the growth plate mechanism.

[PMID:28696225] [INDIRECT EVIDENCE] [SUPPORT] Hedgehog (Hh) signaling is significantly reduced in the long bones of these embryos --- Explanation: Reduced Hedgehog signaling in long bones of GPC6-null mice directly explains the limb shortening phenotype.

[PMID:9508243] [INDIRECT EVIDENCE] [SUPPORT] The pathological characteristics of the omodysplastic physeal plates were an expanded zone of proliferating cartilage and an increased number of closely packed, small chondrocytes --- Explanation: Histomorphometric analysis of an omodysplastic fetus directly demonstrates growth plate chondrocyte abnormalities, with compensatory hyperplasia of small chondrocytes.

[PMID:37353964] [INDIRECT EVIDENCE] [SUPPORT] the variant found in this family results in significantly reduced stimulation of Hh activity when compared to the wild-type GPC6 protein, however protein function is still present --- Explanation: Hedgehog reporter assay demonstrates that GPC6 missense variant p.Arg171Trp causes reduced but not abolished Hh signaling, explaining the milder phenotype and confirming Hh as the key pathway.


MAXO:0000004


MAXO:0000011


MAXO:0000079


hgnc:4454

[PMID:19481194] [SUPPORT] autosomal-recessive omodysplasia, a genetic condition characterized by short-limbed short stature, craniofacial dysmorphism, and variable developmental delay, maps to chromosome 13 (13q31.1-q32.2) and is caused by point mutations or by larger genomic rearrangements in glypican 6 (GPC6) --- Explanation: Maps the disease locus and identifies the causative gene with the spectrum of mutation types.

[PMID:32655339] [SUPPORT] A homozygous deletion of exon 6 in the GPC6 gene was detected --- Explanation: Confirms that larger genomic rearrangements (exon deletions) in GPC6 also cause the recessive form.

[PMID:37353964] [SUPPORT] All affected individuals were found to have homozygous missense variants in GPC6: c.511 C>T (p.Arg171Trp) --- Explanation: Identifies a hypomorphic GPC6 missense variant causing a milder skeletal dysplasia phenotype, expanding the mutation spectrum beyond truncating mutations.


hgnc:4040

[PMID:25759469] [SUPPORT] The FZD2 mutation (c.1644G>A) changes a tryptophan residue at amino acid 548 to a premature stop (p.Trp548*) --- Explanation: First identification of the p.Trp548* nonsense mutation in FZD2 as the cause of autosomal dominant omodysplasia.

[PMID:29383834] [SUPPORT] Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2. The affected codon was next to the previously reported mutation (p.Trp548*) --- Explanation: Second FZD2 nonsense mutation at an adjacent codon confirms a mutational hotspot in the C-terminal Dishevelled-interacting domain.

[PMID:30455931] [SUPPORT] two patients with autosomal dominant omodysplasia and mutations in the FZD2 gene. The mutations identified have been recently reported, suggesting the possibility of recurrent mutations --- Explanation: Additional unrelated patients with FZD2 mutations support recurrence at the same hotspot.

[PMID:29230162] [SUPPORT] a heterozygous de novo mutation (G434V) in the frizzled class receptor 2 (FZD2) gene in a patient with distinct facial features including hypertelorism, bilateral cleft lip/palate, short nose with a broad nasal bridge, microretrognathia, and bilateral shortness of the upper limbs --- Explanation: Identifies a missense FZD2 mutation (G434V) distinct from the C-terminal nonsense hotspot, expanding the mutation spectrum to include missense variants and broadening the phenotypic range to include cleft lip/palate.


MONDO:0017136

[PMID:19481194] [SUPPORT] autosomal-recessive omodysplasia, a genetic condition characterized by short-limbed short stature, craniofacial dysmorphism, and variable developmental delay, maps to chromosome 13 (13q31.1-q32.2) and is caused by point mutations or by larger genomic rearrangements in glypican 6 (GPC6) --- Explanation: Identifies GPC6 as the causative gene for autosomal recessive omodysplasia via linkage mapping and mutation analysis.


MONDO:0017136

[PMID:25759469] [SUPPORT] We identified a de novo mutation in FRIZZLED2 (FZD2) in the proband and her daughter that was not found in unaffected family members --- Explanation: First identification of FZD2 as the causative gene for autosomal dominant omodysplasia.

[PMID:29383834] [SUPPORT] Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2. The affected codon was next to the previously reported mutation (p.Trp548*) --- Explanation: Confirms recurrent de novo nonsense FZD2 mutations in the C-terminal domain as the cause of autosomal dominant omodysplasia.


MONDO:0017137

[PMID:16714198] [SUPPORT] Skin symptoms are commonly nonspecific and include severe pruritus, acute and chronic dermatitis --- Explanation: Severe pruritus is a common skin symptom of onchocerciasis.


MONDO:0017137

[PMID:16714198] [SUPPORT] Skin symptoms are commonly nonspecific and include severe pruritus, acute and chronic dermatitis --- Explanation: Dermatitis is listed among common skin symptoms.


MONDO:0017137

[PMID:16714198] [SUPPORT] Onchocercal ocular disease covers a large spectrum of manifestations, which in severe cases, may lead to blindness. --- Explanation: Severe ocular disease can lead to blindness.


MAXO:0000058

[PMID:16714198] [SUPPORT] Ivermectin is, at present, the drug of choice for skin and ocular manifestations. --- Explanation: The abstract identifies ivermectin as the drug of choice.


NCBITaxon:6282

[PMID:16714198] [SUPPORT] Onchocerciasis results from infestation by the nematode Onchocerca volvulus --- Explanation: The abstract identifies O. volvulus as the causative nematode.


MONDO:0009785

[PMID:40504975] [SUPPORT] INPPL1-related opsismodysplasia is characterized by prenatal-onset short stature, short, bowed limbs, characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, relatively long philtrum). --- Explanation: GeneReviews entry establishing the cardinal features of the disorder.


MONDO:0009785

[PMID:23273569] [SUPPORT] Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. --- Explanation: Micromelia with short hands and feet is a defining feature.


MONDO:0009785

[PMID:23552673] [SUPPORT] Opsismodysplasia is an autosomal recessive skeletal disorder characterized by facial dysmorphism, micromelia, platyspondyly and retarded bone maturation. --- Explanation: Platyspondyly is listed as a cardinal feature.


MONDO:0009785

[PMID:6496568] [SUPPORT] very retarded bone maturation; marked shortness of the bones of the hands and of the feet with concave metaphyses; and thin, lamellar vertebral bodies. --- Explanation: Original disease description emphasizing delayed bone maturation as a cardinal feature.


MONDO:0009785

[PMID:39911177] [SUPPORT] Opsismodysplasia is a rare autosomal recessive genetic skeletal disorder characterized by short stature, short limbs, small hands and feet, delayed bone age, severe platyspondyly, metaphyseal cupping, and facial dysmorphism. --- Explanation: Metaphyseal cupping is listed among the defining radiographic features.


MONDO:0009785

[PMID:40504975] [SUPPORT] INPPL1-related opsismodysplasia is characterized by prenatal-onset short stature, short, bowed limbs, characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, relatively long philtrum). --- Explanation: Relative macrocephaly is listed among the characteristic facial features.


MONDO:0009785

[PMID:40504975] [SUPPORT] INPPL1-related opsismodysplasia is characterized by prenatal-onset short stature, short, bowed limbs, characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, relatively long philtrum). --- Explanation: Prominent forehead (frontal bossing) is a characteristic facial feature.


MONDO:0009785

[PMID:40504975] [SUPPORT] INPPL1-related opsismodysplasia is characterized by prenatal-onset short stature, short, bowed limbs, characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, relatively long philtrum). --- Explanation: Midface retrusion is among the characteristic facial features.


MONDO:0009785

[PMID:40504975] [SUPPORT] INPPL1-related opsismodysplasia is characterized by prenatal-onset short stature, short, bowed limbs, characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, relatively long philtrum). --- Explanation: Depressed nasal bridge is among the characteristic facial features.


MONDO:0009785

[PMID:40504975] [SUPPORT] INPPL1-related opsismodysplasia is characterized by prenatal-onset short stature, short, bowed limbs, characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, relatively long philtrum). --- Explanation: Short nose is among the characteristic facial features.


MONDO:0009785

[PMID:40504975] [SUPPORT] INPPL1-related opsismodysplasia is characterized by prenatal-onset short stature, short, bowed limbs, characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, relatively long philtrum). --- Explanation: Anteverted nares is among the characteristic facial features.


MONDO:0009785

[PMID:40504975] [SUPPORT] INPPL1-related opsismodysplasia is characterized by prenatal-onset short stature, short, bowed limbs, characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, relatively long philtrum). --- Explanation: Long philtrum is among the characteristic facial features.


MONDO:0009785

[PMID:40504975] [SUPPORT] INPPL1-related opsismodysplasia is characterized by prenatal-onset short stature, short, bowed limbs, characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, relatively long philtrum). --- Explanation: Bowed limbs are listed as a characteristic feature.


MONDO:0009785

[PMID:40504975] [SUPPORT] INPPL1-related opsismodysplasia is characterized by prenatal-onset short stature, short, bowed limbs, characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, relatively long philtrum). --- Explanation: Delayed epiphyseal mineralization is a hallmark feature described in GeneReviews.


MONDO:0009785

[PMID:40209709] [SUPPORT] We demonstrate that inppl1a-dependent vacuolated cell expansion is essential to establish normal mechanical properties of the notochord and to facilitate the development of a straight spine. --- Explanation: Zebrafish inppl1a mutants develop scoliosis, supporting this phenotype in the INPPL1-related disease spectrum.


MONDO:0009785

[PMID:17315533] [SUPPORT] Both children had hypophosphatemia, decreased TRP, and rickets. --- Explanation: Documents hypophosphatemic rickets in opsismodysplasia patients.

[PMID:17315533] [SUPPORT] We now demonstrate an association between opsismodysplasia, hypophosphatemic rickets, and FGF23 elevation. --- Explanation: Establishes the association with FGF23-mediated phosphate wasting.


MONDO:0009785

[PMID:26157786] [SUPPORT] Renal phosphate wasting is associated with severe bone demineralization and a more severe phenotype. --- Explanation: Bone demineralization is a feature, exacerbated by phosphate wasting.


MONDO:0009785

[PMID:6496568] [SUPPORT] very retarded bone maturation; marked shortness of the bones of the hands and of the feet with concave metaphyses; and thin, lamellar vertebral bodies. --- Explanation: Short feet with concave metaphyses are defining features from the original description.


MONDO:0009785

[PMID:6496568] [SUPPORT] very retarded bone maturation; marked shortness of the bones of the hands and of the feet with concave metaphyses; and thin, lamellar vertebral bodies. --- Explanation: Short hands with concave metaphyses are defining features from the original description.


MONDO:0009785

[PMID:23273569] [INDIRECT EVIDENCE] [SUPPORT] INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. --- Explanation: Identifies the enzymatic function of INPPL1/SHIP2 in phosphoinositide signaling.

[PMID:27708270] [INDIRECT EVIDENCE] [SUPPORT] skeletal disease seems to result from the loss of SHIP2 activity due to catalytic domain mutations or no SHIP2 protein due to premature stop codons. --- Explanation: Confirms that loss of SHIP2 enzymatic activity is the pathogenic mechanism.

[PMID:24953221] [INDIRECT EVIDENCE] [SUPPORT] Inppl1 catalytic activity is critical for normal bone development. --- Explanation: Demonstrates that SHIP2 catalytic function is required for skeletal development, based on mouse knockout data cited by Li et al.

[PMID:27233067] [INDIRECT EVIDENCE] [SUPPORT] The absence of SHIP2 was confirmed by immunoblot analysis of proband amniocytes. --- Explanation: Direct protein-level evidence showing complete loss of SHIP2 in a patient with compound heterozygous INPPL1 variants.


MONDO:0009785


MONDO:0009785

[PMID:31519471] [INDIRECT EVIDENCE] [SUPPORT] levels of p-MEK and p-Erk1/2 were significantly increased in SHIP2-inactivated chondrocytes in response to serum and IGF-1. --- Explanation: Mouse model demonstrates that SHIP2 loss increases MEK-Erk1/2 signaling in chondrocytes.

[PMID:31519471] [INDIRECT EVIDENCE] [SUPPORT] Treatment of chondrocytes and bones in culture with a MEK inhibitor partially rescued the production of mineralized nodules, the size of the hypertrophic chondrocyte zone and bone growth. --- Explanation: MEK inhibition partially restores mineralization, confirming MEK-Erk1/2 pathway involvement.

[PMID:6496568] [INDIRECT EVIDENCE] [SUPPORT] The growth cartilage studied in one case showed a wide hypertrophic area containing thick connective tissue septa, irregular provisional calcification, and vascular invasion. --- Explanation: Original description of growth plate histopathology in opsismodysplasia.

[PMID:23273569] [INDIRECT EVIDENCE] [SUPPORT] Our finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this enzyme in endochondral ossification. --- Explanation: Links INPPL1 mutations to growth plate disorganization and impaired endochondral bone formation.


MONDO:0009785

[PMID:28869677] [INDIRECT EVIDENCE] [SUPPORT] cell migration is very much decreased in fibroblasts derived from three OPS patients as compared with control individuals. --- Explanation: Patient fibroblasts directly demonstrate impaired migration due to SHIP2 deficiency.

[PMID:28869677] [INDIRECT EVIDENCE] [SUPPORT] signaling events linked to migration and particularly to adhesion, which are lost in OPS patients, would prevent normal endochondral ossification. --- Explanation: Links cell migration and adhesion defects to the skeletal phenotype.


MONDO:0009785

[PMID:17315533] [INDIRECT EVIDENCE] [SUPPORT] We now demonstrate an association between opsismodysplasia, hypophosphatemic rickets, and FGF23 elevation. --- Explanation: First report demonstrating the link between opsismodysplasia and FGF23-mediated phosphate wasting.

[PMID:26157786] [INDIRECT EVIDENCE] [SUPPORT] Renal phosphate wasting is associated with severe bone demineralization and a more severe phenotype. --- Explanation: Establishes that phosphate wasting worsens the skeletal phenotype.


MAXO:0000954

[PMID:26157786] [SUPPORT] This report represents the first described cases of opsismodysplasia treated with intravenous bisphosphonate (pamidronate). --- Explanation: First report of bisphosphonate use in opsismodysplasia.

[PMID:26157786] [SUPPORT] At 10 years of age, he has stopped taking his wheelchair to school and runs during recess, demonstrating a remarkable progress presumably related to his pamidronate usage. --- Explanation: Demonstrates functional motor improvement with bisphosphonate therapy.

[PMID:40504975] [SUPPORT] Intravenous bisphosphonate therapy has improved bone mineral density and gross motor function in two individuals with INPPL1-related opsismodysplasia. --- Explanation: GeneReviews confirms bisphosphonate benefit for bone density and motor function.

[PMID:40620719] [SUPPORT] Pamidronate is effective in treating OPS even in the absence of hypophosphatemic rickets, showing potential as a therapeutic option for this rare condition. --- Explanation: Demonstrates efficacy of pamidronate even without phosphate wasting.


MAXO:0000058

[PMID:17315533] [SUPPORT] Oral phosphorus and calcitriol improved metaphyseal mineralization, yet serum phosphate levels remained relatively low and renal phosphate wasting persisted. --- Explanation: Directly documents the treatment response to phosphate and calcitriol supplementation.