|Year : 2021 | Volume
| Issue : 3 | Page : 167-176
Pathogenesis and therapy of arteriovenous malformations: A case report and narrative review
Steven Tessier1, Brooke A Lipton1, Firas Ido2, Santo Longo3, Sudip Nanda4
1 Lewis Katz School of Medicine, Temple University, Philadelphia, USA
2 Department of Pulmonary and Critical Care, St. Luke's University Health Network, Bethlehem, PA, USA
3 Department of Pathology, St. Luke's University Health Network, Bethlehem, PA, USA
4 Department of Cardiology, St. Luke's University Health Network, Bethlehem, PA, USA
|Date of Submission||22-Jul-2020|
|Date of Decision||24-Oct-2020|
|Date of Acceptance||05-Jan-2021|
|Date of Web Publication||25-Sep-2021|
Dr. Sudip Nanda
Department of Cardiology, St. Luke's University Health Network, Bethlehem, Pennsylvania
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Arteriovenous malformations (AVMs) are abnormal communications between arteries and veins that lack intervening capillary beds. They have been described in almost every organ in the body, emerging sporadically or as part of well-described syndromes. Hereditary hemorrhagic telangiectasia (HHT) is a rare, progressive, and lifelong disease characterized by AVMs and recurrent hemorrhaging. In the last 2 decades, significant advances have been made in understanding the pathogenesis of this condition. The accumulation of knowledge has led to a natural evolution of therapy, from open surgery to endovascular procedures, and now to a role for medications in certain AVMs. Here, we review a case of HHT and describe the most up-to-date clinical practice, including diagnosis of HHT, subtypes of HHT, and medical therapy.
Keywords: Arteriovenous malformation, case report, hereditary hemorrhagic telangiectasia, transforming growth factor-β signaling
|How to cite this article:|
Tessier S, Lipton BA, Ido F, Longo S, Nanda S. Pathogenesis and therapy of arteriovenous malformations: A case report and narrative review. Int J Crit Illn Inj Sci 2021;11:167-76
|How to cite this URL:|
Tessier S, Lipton BA, Ido F, Longo S, Nanda S. Pathogenesis and therapy of arteriovenous malformations: A case report and narrative review. Int J Crit Illn Inj Sci [serial online] 2021 [cited 2021 Dec 5];11:167-76. Available from: https://www.ijciis.org/text.asp?2021/11/3/167/326594
| Introduction|| |
Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder. It is named for progressive lifelong recurrent hemorrhages associated with and due to large and small vascular malformations. Respectively, these are arteriovenous malformations (AVM) and telangiectasias (TeLs). AVM formation can be congenital or acquired. Definitive diagnosis requires at least three of the four widely used International Curacao criteria: (1) epistaxis, (2) mucocutaneous TeLs, (3) AVMs, and (4) family history. The patient described in this case study has all four.
| Case Report|| |
A 75-year-old male without known coronary artery disease presented to the emergency department with acute-onset chest pain. His medical history was significant for recurrent epistaxis. Physical examination was normal except for superficial lip TeLs [Figure 1]a. Vital signs included a heart rate of 67 beats/min, blood pressure of 159/80 mmHg, respiratory rate of 18 breaths/min, and oxygen saturation of 87% when breathing ambient air. The complete blood count revealed erythrocytosis with a hemoglobin of 16.9 g/dL and hematocrit of 50.4. Electrocardiogram demonstrated nonspecific ST segment changes in the inferior leads and serial cardiac troponin peaked at 40 ng/ml. Immediate medical therapy included aspirin 325 mg in combination with ticagrelor 180 mg, intravenous heparin infusion, atorvastatin 80 mg, and metoprolol 12.5 mg. Coronary angiography revealed significant multivessel disease. Echocardiogram showed a left ventricular ejection fraction of 50% without evidence of pulmonary hypertension (PH); however, inferolateral hypokinesis and moderate ventricular hypertrophy were noted. A nonemergent coronary artery bypass graft (CABG) was recommended and preoperative testing was performed.
|Figure 1: (a) Lip telangiectasias (arrows). (b) Left upper lobe arteriovenous malformation (arrow). (c) Left upper and right lower lobe arteriovenous malformations (arrows). (d) Three-dimensional reconstruction with arteriovenous malfomation isolation. (e) Right occipital lobe infarct. (f) Posterior cerebral artery narrowing of P2 and P3 segments|
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In preparation for CABG, bilateral carotid ultrasound did not indicate significant atherosclerotic disease. A chest X-ray showed several nondiagnostic pulmonary nodular densities which were identified by a contrast-enhanced chest computed tomography (CT) as pulmonary AVMs (PAVMs). Three-dimensional reconstruction provided detailed configuration and distribution of the PAVMs [Figure 1]b, [Figure 1]c, [Figure 1]d. The patient recalled hemoptysis and hemorrhagic strokes involving both his father and brother. Pulmonary function test revealed normal spirometry and lung volumes and a reduced carbon monoxide diffusion capacity. The periodic hypoxia captured on pulse oximetry was verified with arterial blood gas analysis, which demonstrated a pH of 7.44, pCO2 of 30 mmHg, pO2 of 54 mmHg, and O2 saturation of 89%. The calculated alveolar–arterial gradient (A-a gradient) was elevated at 58 mmHg. Causes of increased A-a gradients include ventilation/perfusion mismatch (i.e., chronic obstructive pulmonary disease [COPD] and pulmonary embolism), diffusion limitations (i.e., pulmonary fibrosis and interstitial lung disease), and both physiologic and anatomic shunts such as atelectasis or pulmonary edema and intracardiac or pulmonary vascular shunts, respectively. Despite supplemental oxygen, the hypoxemia failed to improve, highlighting a unique feature of the right-to-left shunt that accompanies PAVMs. Immediate intervention of the PAVMs was postponed and CABG prioritized. Brain magnetic resonance imaging (MRI) to screen for additional AVMs was negative; however, several bilateral chronic lacunar infarctions were detected in the cerebellum.
Postoperatively, aspirin 325 mg daily, atorvastatin 40 mg daily, and cardiopulmonary rehabilitation were initiated; however, beta-blocker and ACE inhibitor were postponed due to the development of sinus bradycardia and acute kidney injury. New-onset atrial fibrillation with tachycardia occurred on postoperative day 3 and therefore apixaban 5 mg twice daily and metoprolol tartrate 12.5 mg twice daily were commenced. Following his discharge, physical rehabilitation and outpatient cardiology evaluation were maintained.
Three weeks following discharge, he returned to the emergency department with symptoms of blurry vision and an unsteady gate. Vital signs were normal and electrocardiogram demonstrated normal sinus rhythm. A noncontrast CT and contrast-enhanced MRI of the brain revealed an evolving subacute stroke with microhemorrhages in the right occipital lobe [Figure 1]e. Multiple imaging studies for an embolic source included carotid magnetic resonance angiography (MRA), repeat echocardiogram, and lower extremity venous duplex which were negative. MRA of the brain to assess for an aneurysm or clot amenable to endovascular intervention was negative; however, multifocal segmental narrowing of the right posterior cerebral artery was present [Figure 1]f. The symptoms subsided, and following discharge, evaluation by interventional radiology recommended PAVM embolization and genetic testing to allow accurate testing of family members. The patient was also referred to gastroenterology to undergo screening for possible abdominal–visceral AVMs.
| Methods|| |
A literature search restricted to the English language was conducted using PubMed to identify articles related to HHT. The search included the MeSH: “Arteriovenous Malformations” and “Telangiectasia, Hereditary Hemorrhagic,” and non-MeSH terms “molecular,” “brain,” “cerebral,” “intracranial,” “pulmonary,” “lung,” “hepatic,” “liver,” “gastrointestinal,” “therapy,” “treatment,” and “prevalence”. The articles were assessed for relevance (pathogenesis and clinical therapy), with particular attention paid to recent findings, the molecular basis of AVM formation, and organ-specific AVM involvement. Furthermore, ClinicalTrials.gov was searched for clinical trials investigating medical approaches to AVMs [Table 1]. Appraisal of the literature and extraction of information was performed by two independent reviewers. Screening of the titles and abstracts was performed first, followed by a critical examination of each article and its findings. The final count of articles used was 89: 38 human experimental studies, 21 basic science/animal studies, 10 case reports/series, 10 reviews, 6 epidemiological studies, and 4 guideline studies. The Critical Appraisal Skills Programme (CASP) checklist was used to ascertain study quality and mitigate risk of bias (https://casp-uk.net/casp-tools-checklists/). The checklists contain criteria on items such as selection bias, measurement or classification bias, confounding factors, validity, precision, and population. The reviewers appraised the studies by assigning the items as positive (if an item was present), negative (if an item was absent), or can't tell/not applicable. The number of items rated positively was divided by the number of applicable items to yield a “CASP score” as a percentage. High-scoring studies represent lower risk of bias, whereas low-scoring studies represent higher risk of bias. CASP scores are shown for the medical therapy studies summarized in [Table 1].
| Discussion|| |
Case report: A clinical challenge
The strength in the approach to the case was the ability to solidify the diagnosis clinically by obtaining a detailed history encompassing symptoms, family history, recognition of physical examination findings (lip TeLs), laboratory values that coincided with PAVMs (erythrocytosis, likely due to chronic hypoxia and the elevated A-a gradient refractory to supplemental oxygen), as well as obtaining the CT of the chest following recognition of nodular densities on chest X-ray. The limitations to our approach were twofold: diagnostic and therapeutic. Diagnostically, we did not have genetic confirmation (although the patient met all clinical criteria). More importantly, we did not have the opportunity to screen for additional AVMs (hepatic, gastrointestinal) before CABG. Although no bleeding complications occurred, the need for antiplatelet therapy following CABG and anticoagulation for atrial fibrillation placed the patient at high risk for bleeding. A catastrophe may have unfolded if he had developed a gastrointestinal bleed from an AVM when on anticoagulation. The second diagnostic limitation was the inability to definitively determine the cause of the stroke. In the setting of large PAVMs, the obvious concern was a paradoxical embolism. However, the etiology was not determined and presumed to be related to atrial fibrillation, although the patient reported compliance with anticoagulation and the MRA of the brain showed stenosis of the vasculature supplying the area of infarction. The final limitation was the therapeutic approach. Closure of the PAVMs was considered a major procedure and would have delayed CABG significantly. The other therapeutic limitation was the choices of therapy following the cerebral infarct. The patient had confirmed atrial fibrillation with a history of chronic cerebellar stroke necessitating anticoagulation; however, he had areas of microhemorrhage and therefore the bleeding risk versus benefit in continuing anticoagulation was challenging.
Hereditary hemorrhagic telangiectasia subtypes
The global prevalence of HHT is 1 in 5,000–10,000, with a higher estimate in Europe and Japan (1 in 5000–8000)., Interestingly, the highest rate of 1 in about 1300 occurs within the populace of the Netherlands Antilles islands of Bonaire and Curacao. HHT is characterized by several subtypes with varying phenotypic manifestations that reflect specific genetic mutations. To date, loss-of-function mutations in the transforming growth factor-β (TGF-β)/bone morphogenic protein (BMP) signaling pathway are the only known causes of HHT. The various clinical phenotypes of HHT are the result of dysregulations of four well-recognized genes within the TGF-β/BMP pathway. They include ENG, (endoglin); ACVRL1 (activin A receptor type II-like kinase1 or ALK1), MADH4 (SMAD4), and GDF2 (Growth Differentiation Factor 2, aka BMP9). A given HHT subtype presents variable expressivity, even among the members of the same afflicted family, indicating notable inter- and intrafamilial variability of disease expression. Notably, nearly all of patients with HHT experience recurrent epistaxis at some point in their lives. [Table 2] shows significant clinical highlights of each subtype.
Molecular basis of arteriovenous malformation formation
AVMs result from an abnormality of angiogenesis. The basic pathways involved are illustrated in [Figure 2].
|Figure 2: Schematic illustrating the role of TGF-β signaling in HHT. The proteins affected by mutations that cause HHT are bolded. (A) BMP9 binds to its receptor (i.e. ALK1) on the surface of an endothelial cell. ENG functions as a co-receptor. Induction of SMAD4 promotes anti-angiogenic gene regulation. (B) PI3K/AKT-mediated VEGF signaling drives endothelial cell proliferation and angiogenesis. ALK1-dependent signaling inhibits PI3K, thus contributing to the balance of anti- and pro-angiogenic intracellular states. (C) ANGPT2 functions as an agonist when its concentrations are greater than ANGPT1, and as an antagonist when its concentrations are less than ANGPT1. (D) ENG plays a role in integrin-mediated adhesion between vascular endothelial and mural cells to promote vessel stabilization|
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The dynamics of blood vessel remodeling are influenced by the antiangiogenic activities of ALK1 and endoglin. ALK1 is a BMP9 and BMP10 receptor that signals through mothers against decapentaplegic homolog-1, -5, and -8 (SMAD1/5/8). SMAD1/5/8 in turn complex with and activate the transcription factor SMAD4. In the nucleus, SMAD4 interacts with transcriptional modulators to promote antiangiogenic gene regulation, including inhibition of angiopoietin-2 (ANGPT2) transcription [Figure 2]a., ALK1 signaling also downregulates angiogenesis by inhibiting PI3K/AKT/mTOR, a common downstream pathway of vascular endothelial growth factor (VEGF) signaling [Figure 2]b. Experimentally, this was well demonstrated by Ola et al., who showed that ALK1 deletion in mice disinhibits PI3K/AKT, resulting in hyperproliferation of endothelial cells and AVM formation. The authors further showed that pharmacological inhibition of P13K rescues these abnormalities. The PI3K/AKT pathway can also be induced by binding of ANGPT2 to its receptor, TIE2. This induction mechanism is context dependent: ANGPT2 functions as an agonist when its concentrations are in excess over its partner TIE2-agonsit, ANGPT1, and as an antagonist when its concentrations are less than ANGPT1 [Figure 2]c. Similar to Ola et al., recent investigations revealed that inhibition of ANGPT2 mitigates AVM formation and improves blood vessel diameter in SMAD4 knockout mice.
Endoglin is an accessory coreceptor for ALK1. Therefore, ALK1 and endoglin jointly inhibit angiogenesis [Figure 2]a. Interestingly, endoglin also plays a role in regulating the stabilization and permeability of the endothelial barrier; in addition to its function as a coreceptor, its RDG motif serves as a ligand for the β1-integrins of pericytes and smooth muscle cells [Figure 2]d. With these mechanisms in mind, one can appreciate how mutations in the genes encoding BMP9, ALK1, endoglin, and SMAD4 lead to formation of AVMs characteristic of HHT.
An engrossing aspect of HHT vascular lesions is that they occur with certain “tropism” for specific organ systems, mucosa, and dermal surfaces, as opposed to manifesting in a diffuse nature. Efforts to explain this phenomenon have put forth the “two-hit” hypothesis. The two-hit hypothesis emerged from observations that a given challenge or assault, such as vascular injury, prompts endothelial cells to upregulate expression of survival factors including endoglin. The hypothesis suggests that mutations in such survival genes (Hit #1) decrease the threshold for endothelial cell survival when stressed by external factors (Hit #2). Evidence for this hypothesis is provided by several studies. For example, mice with a deficiency in endoglin (Hit #1) develop AVMs when exposed to the angiogenic factors VEGF and basic fibroblast growth factor (Hit #2). Likewise, while mice with a deficiency in ALK1 (Hit #1) exhibit pulmonary and gastrointestinal hemorrhaging, an inductive factor such as wounding (Hit #2) is required to initiate the formation of dermal AVMs. Topically applied VEGF-blockade (inhibition of Hit #2) can prevent dermal AVM formation in a wounding mouse model of HHT.
Pulmonary arteriovenous malformations
More than 70% of PAVMs are ascribed to HHT and about 50% of HHT patients are affected by PAVMs., PAVMs serve as anatomical right-to-left shunts, bypassing the alveolar–capillary interface and resulting in hypoxemia. PAVMs increase the risk of paradoxical emboli, which can result in stroke, visceral infarction, and acute limb ischemia., Paradoxical embolisms originate from a dislodged venous thrombus that travels through a right-to-left shunt to the systemic circulation. Such shunts can be intracardiac (i.e., patent foramen ovale or atrial/ventricular septal defects), or extracardiac (i.e., PAVM), as most often is the case in HHT. PAVMs may also be asymptomatic, but still increase risk of potentially life-threatening yet preventable complications.
Anatomically, PAVMs are malformations that allow direct communication between the pulmonary and systemic circulations in the absence of normal capillary connections. They most commonly consist of a supplying artery, a draining vein, and a set of irregularly arranged anomalous vessels, collectively called a nidus. The nidus serves as a high-flow conduit connecting the supplying artery and draining vein, thus circumventing conventional capillary beds. This type of PAVM, in which a single segmental pulmonary artery is involved, is subclassified as “simple.” A “complex” PAVM is noted when two or more pulmonary artery branches are involved. These are important considerations for planning endovascular intervention, especially since transcatheter embolotherapy is widely accepted as the benchmark treatment for this condition. When treatment via embolization is unsuccessful or not possible, lobectomy may be considered as a second option. It may also be the preferred modality when patients are symptomatic, have a more complicated case of PAVM, or when PAVM diagnosis is not possible.
Neurovascular complications are frequently encountered by patients with HHT. In general, these can be characterized as being primary conditions, in which case spinal or cerebral AVMs (CAVMs) are present, or secondary events such as paradoxical emboli, enabled by right-to-left shunting.
An estimated 10%–20% of HHT patients suffer from CAVMs., CAVMs are classified into three subtypes on account of radiologic and angiographic studies. These include (1) small, nonshunting “capillary vascular malformations;” (2) the classic, shunting “nidus-type,” where pial vessels are typically the feeding arteries; and (3) high-volume, single-hole “fistulous” AVMs which lack nidi, also called arteriovenous fistulas (AVFs). About more than 60% of nidus-type CAVMs are discovered incidentally, reflecting their tendency to be asymptomatic, although about 15% of patients with HHT and CAVMs suffer intracranial hemorrhage. While AVFs are the least common CAVM, they are prone to poor angioarchitecture that may complicate patient history. These may include associated aneurysms of engorged feeding arteries, moyamoya-type alterations, arteriostenosis, and venous dilation. Therefore, symptoms of AVFs include those associated with increased intracranial pressure, headache, bruit, hemorrhage, and seizures, as well as congestive cardiac manifestations and altered mental state.,, Of note, spinal cord AVMs, predominantly occurring in the pediatric HHT population with a prevalence of roughly 1%, may present alongside complaints of back pain and/or paralysis.,
Secondary conditions resulting from cerebral embolic complications in patients with HHT include cerebral abscesses and ischemic stroke. Although exceedingly rare in the general population (<1 in 100,000 people per year), they are common in individuals with HHT and PAVMs, since cerebral abscesses are frequently secondary to septic emboli facilitated by intrapulmonary shunt., Accordingly, prophylactic treatment measures are recommended for cerebral abscesses, such as antibiotic administration before invasive procedures and coil embolization of PAVMs.
Ischemic stroke occurs more frequently in HHT patients with PAVMs. Stroke may also result from hyperviscosity due to secondary erythrocytosis caused by chronic right-to-left shunt hypoxemia or gas emboli secondary to communication between airway and pulmonary circulation. Stroke rates in these patients can be markedly reduced by obliteration of PAVMs.
Involvement of the liver in HHT patients is most commonly associated with HHT2. In large prospective studies, the prevalence of hepatic involvement in HHT patients has ranged from 41% to 78%. Clinical presentation varies as most cases involve TeL which are largely asymptomatic. However, due to the dual blood supply of the liver, large shunts can form in one of three types that may coexist: (1) “arteriovenous,” the most common, (2) “arterioportal,” and (3) “portovenous.” In a multidetector row helical CT multiphasic study of 78 HHT patients with hepatic involvement, it was found that arterioportal shunts occurred in 50% of cases, arteriosystemic shunts in 20% of cases, and both shunt types in about 30% of cases. Buscarini et al. determined that morbidity and mortality is increased considerably by these hepatic shunts; out of 154 patients, 25.3% experienced complications from hepatic AVMs (HAVMs) and 5.2% died from AVM-related complications. In a study analyzing the clinical findings of 19 HHT patients with HAVMs, typical clinical presentations included high cardiac output failure, portal hypertension, and biliary disease. Hepatic artery dilation, elevated hepatic artery flow, and intrahepatic hypervascularity are also associated with HAVMs.
HAVMs can be graded using doppler ultrasonography into the categories of minimal (hepatic artery measures >6 mm and is dilated in extrahepatic tract), moderate (hepatic artery is dilated in both intra and extrahepatic tract), or severe (arterial hepatic branches are associated with hepatic and/or portal vein dilation). In a cohort of 92 patients with HHT and hepatic involvement, 12% of HAVMs were minimal, 76% were moderate, and 12% were severe. Aside from ultrasonography, HAVMs can be detected using MRI, triphasic spiral CT, and mesenteric angiography.
PH is an increasingly recognized complication of HHT and is frequently described in HHT2. PH most often presents as postcapillary hypertension secondary to HAVMs, associated with high cardiac output and heart failure. Precapillary hypertension is a rarer cause of PH in HHT patients, wherein cardiac output is normal or decreased, but pulmonary vascular resistance is increased due to the remodeling of small pulmonary arteries.
Treatments for HAVMs include hepatic artery embolization and liver transplantation. Hepatic artery embolization reduces arteriovenous and arterioportal shunting and can alleviate heart failure and mesenteric steal syndrome. However, it has been recommended that hepatic artery embolization be avoided if possible due to its relatively high association with morbidity and mortality, as well as the temporality of the alleviation of symptoms. The majority of patients experience an alleviation of symptoms following liver transplant, although postoperative complications must be considered.,
Gastrointestinal bleeding is a common symptom of HHT, occurring in up to 33% of HHT patients and with an onset of about 50 years of age. Gastrointestinal manifestations include esophageal, gastric, and small-bowel TeLs, small-bowel polyps and masses, and colonic vascular malformations. Such vascular lesions can lead to chronic hemorrhage and anemia, requiring blood transfusion and/or iron supplementation. The most common lesions occur in the stomach, especially of the fundus, and the small intestine. In patients with HAVMs and associated portal hypertension, esophageal varices are also prone to hemorrhage. Therefore, the international HHT guidelines advise the monitoring of hemoglobin and serum iron levels starting at 35 years of age and recommend that endoscopy be performed if anemia develops to an extent that is not explained by the severity of epistaxis. In addition to supportive care, argon plasma coagulation and long-acting somatostatin analog therapy may be effective treatments for recurrent anemia and gastrointestinal hemorrhaging in patients with HHT.,
While open and endovascular surgeries remain the mainstay for AVM treatment, insight into pathogenesis has given us options on how to potentially treat this condition medically. There are a number of drugs that have been proposed as therapeutic agents for the treatment of HHT, including antiangiogenic pharmaceuticals, as well as suggestions to repurpose commonly used drugs such as metformin and propranolol. A commonality between most of these is their antiangiogenic properties and the usage of endoglin and/or ALK1 as direct or indirect targets. These agents have a proven role in the treatment of epistaxis and have a potential role for managing AVMS located in high-risk areas where surgical therapy is associated with high risk of complication. They may also be useful for treating very sick patients with numerous comorbidities. The various available and potentially future therapies are included in [Table 1].
| Conclusion|| |
A diagnosis of HHT on the basis of the international Curacao criteria should lead to a step-wise approach of patient care. First, the involvement of AVMs in specific organ systems, and second, their associated clinical presentations, should be considered as highlighted in [Table 3] and [Table 4]. The provider should ask the questions: Which other organ systems are expected to have AVM involvement? What pertinent symptoms need to be reviewed for each organ system and carefully examined on evaluation? Third, an attempt to identify the patient's subtype of HHT should be invoked, as natural history of disease will allow specific follow-up. Sequencing of patients in question can be especially helpful. It should be noted that there remains a significant number of patients who meet the Curaçao criteria but test negative for mutations in ACVRL1, ENG, MADH4, and GDF2, suggesting that there are HHT-causing mutations that have yet to be unveiled. Genomic analyses and next-generation sequencing of individuals who lack known mutations associated with HHT should facilitate discovery of novel genetic mutations and DNA modifications responsible for causing this disease. Fourth, an understanding of medications that are being tried or are in trials can add great value to the course of clinical management.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Research quality and ethics statement
This case report did not require approval by the Institutional Review Board / Ethics Committee. The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines, specifically the CARE guideline, during the conduct of this research project.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]