Episodes Of Edema Research Articles

Prevention of Recurrent Attacks of Hereditary Angioedema (HAE): Berotralstat and Its Oral Bioavailability.

Hereditary angioedema (HAE) is a condition characterized by episodes of cutaneous and submucosal edema. Angioedema of the extremities and abdominal attacks are the most common manifestations of the disease. It can also affect the upper airways with the potential of becoming life-threatening. The two most common causes of HAE are a deficiency of C1 inhibitor (classified as type 1 HAE) or a dysfunction of C1 inhibitor (type 2 HAE). A malfunction or deficiency of C1 inhibitor leads to an overactivated plasma kallikrein (an inflammatory vasoactive peptide), that increases bradykinin, mediating the angioedema episodes in patients with HAE. To minimize the difficulties of this pathology and to improve patients' quality of life, prevention of this condition is essential. Berotralstat is a unique option for oral administration for routine prophylaxis. This drug acts by binding to kallikrein and reducing its plasma activity, lowering bradykinin levels. Open-label studies have demonstrated the effectiveness of a single daily dose of berotralstat 150 mg in preventing HAE attacks. This review aims to examine studies performed to elucidate the efficacy, safety, and tolerability of berotralstat.

Burden of illness seen in hereditary angioedema in Japanese patients: Results from a patient reported outcome survey.

Hereditary angioedema (HAE) is a potentially life-threatening rare disease, which is mainly caused by the deficiency or dysfunction of C1-esterase inhibitor, and characterized by spontaneous, recurrent episodes of edema in various parts of the body including internal organs and the laryngeal area. Delayed diagnosis and treatment increase the burdens and risks of this condition. The current study aimed to understand the burden of illness for HAE patients in Japan before and after diagnosis through a patient reported outcome survey. A survey instrument was distributed to 121 adult patients with HAE by a patient organization via HAE treating physicians between July and November in 2016. Seventy patients (57.9%) returned the questionnaire. Patients reported high levels of medical resource utilization, including emergency procedures and services. Episodes of receiving laparotomy were somewhat less after diagnosis with HAE than before, but no apparent difference in episodes of tracheotomy between before and after the diagnosis. The economic burden, including direct and indirect medical costs, was highest before diagnosis, but still perceived as substantial after diagnosis. Patients reported disruption of work and school life, with 40% reporting that they miss 10 or more days from work or education per year. Sixty percent of patients reported that HAE affected their daily activities. We concluded that HAE is associated with considerable physical, social, economic and psycho-social burdens even after diagnosis, and that higher attack frequency is associated with a heavy disease burden for patients in Japan.

FACIAL SWELLING, RESPIRATORY FAILURE, FLUCTUATING COMPLEMENT 4 LEVELS, AND RELIGIOUS CONSIDERATION IN A PEDIATRIC PATIENT

<h3>Introduction</h3> Hereditary Angioedema is a rare condition defined by acute, recurring episodes of edema, with the upper airway being particularly dangerous. HAE Type 2 is caused by the dysfunction of the C1-esterase inhibitor with low C4 levels. <h3>Case Description</h3> A 10-year-old female presented with facial and airway swelling unresponsive to steroids, antihistamines, and epinephrine that required intubation. C4 complement was low but then was normal prior to treatment. The patient's religion did not allow for plasma products, but a plasma derived C1 esterase inhibitor product was given emergently with improvement in her swelling. C1 Esterase Inhibitor Function was found to be low. A non-formulary recombinant C1 esterase inhibitor product was arranged for hospital and later home use. At 11 years she was admitted in respiratory failure. She decompensated with failed attempts at intubation and required cricothyrotomy. A recombinant C1 esterase inhibitor product was given. She remained with tracheostomy for 7 days then was de-cannulated. She was discharged with an oral plasma Kallikrein inhibitor, emergency recombinant C1 esterase inhibitor product, and a HAE emergency card. In addition to formulary HAE treatment, a recombinant product was placed in restricted use. A best practice advisory was developed in the EMR to advise physicians of the patient's HAE status. <h3>Discussion</h3> Although HAE Type 2 is well characterized, this is a rare report of a Pediatric patient with HAE requiring intubation on initial presentation and later cricothyrotomy. The challenge was her respiratory failure as a presenting sign of HAE, fluctuating C4 levels, religious consideration, and implementation of an EMR advisory.

A CASE OF HEREDITARY ANGIOEDEMA SUBTYPE SWITCH

<h3>Introduction</h3> Hereditary angioedema (HAE) is a condition that is described by recurrent episodes of edema without pruritis that can involve multiple different organ systems including skin, gastroenterological tract, and upper respiratory tract. HAE arises from deficiency or abnormality of C1 inhibitor (C1-INH). HAE can be classified into two different classes. HAE-type I is a deficiency in C1-INH resulting in low plasma protein and abnormal functional C1 esterase level. HAE-type II is a dysfunctional C1-INH resulting in low plasma protein but normal functional C1 esterase. <h3>Case Description</h3> A 54-year-old man presents to his primary care doctor's office with a longstanding history of intermittent abdominal pain and and facial swelling lasting 12-24 hours. He has been evaluated by multiple other specialists including Gastroenterologists without an official diagnosis. He was seen by an Allergist and was diagnosed with HAE- type II after his functional C1 esterase inhibitor was normal, C3 complement was low range, and C4 complement was low. He was diagnosed with lymphoma around the same time of his HAE-type II. He was treated with Danazol and his symptoms resolved. Shortly after, the repeat functional C1 esterase was much lower, C3 and C4 complement was still low. It had appeared that he was now consistent with HAE-type I. <h3>Discussion</h3> This HAE subtype switch has not yet been described in the medical community. HAE is condition that is still misdiagnosed amongst medical specialities given the lack of understanding despite it being commonly reported condition as it may mimic other IgE mediated reactions.

Throat microbiota alterations in patients with hereditary angioedema

BackgroundHereditary angioedema (HAE) is a rare disease characterized by recurrent episodes of cutaneous and submucosal edema. The clinical course of HAE is heterogeneous and unpredictable. There are no reliable indicators associated with angioedema attacks and severity. Throat microbiota plays vital roles in the maintenance of human health, while its association with HAE is barely understood. Therefore, this study aimed to investigate the alteration of throat microbiota and its correlation with attacks severity in HAE patients. MethodsThroat swab samples were collected from HAE patients and their healthy family members, and then subjected to 16S rRNA sequencing. Alpha and beta diversity were used to examine the diversity and structure of bacterial communities. The relative abundance of individual bacteria was compared between study groups to determine the discriminant taxa. Spearman's correlation and linear regression were applied to analyze the correlation between throat bacteria and attacks severity. ResultsIrrespective of the study groups, the throat microbiome was predominantly occupied by Firmicutes, Bacteroidetes, Proteobacteria, and Fusobacteria. The recent onset of laryngeal edema is associated with the altered composition of microbiome community in HAE patients. The relative abundance of Bacteroidetes and Prevotellaceae was significantly increased in patients with recent episodes of laryngeal edema, compared to patients without recent episodes of laryngeal edema. Additionally, HAE attack severity scores positively correlated with the relative abundance of Bacteroidetes. ConclusionWe reported alterations of the throat microbial communities in HAE patients and explored the correlation between bacteria and edema severity, which may shed light on understanding the disease course and developing new therapeutic strategies for HAE.

Concurrent valve replacement and caesarean section for rheumatic mitral valve disease with refractory heart failure in late pregnancy.

To assess clinical characteristics and outcomes of women who underwent concurrent valve replacement with caesarean section for severe rheumatic mitral valve disease with refractory heart failure. All women admitted to a single centre from 2011 to 2020 with severe rheumatic mitral valve disease, having recurrent episodes of pulmonary edema on optimal medical therapy and contraindication to percutaneous balloon mitral valvotomy, who underwent concurrent valve replacement (for native valve disease) along with caesarean section, were included. Among 1300 pregnancies with rheumatic heart disease, six underwent the concurrent procedure. All had replacement of mitral valve except one who had both aortic and mitral valve replacements, between 33 and 39 weeks of gestation. There were no maternal deaths, and there was one neonatal loss from late-onset sepsis. Pregnant women with severe rheumatic mitral valve disease with refractory heart failure, unsuitable for minimal access interventions, can be considered for a concurrent valve replacement with caesarean section.

Prophylactic therapy with subcutaneous C1-inhibitor is associated with sustained symptom control in patients with hereditary angioedema.

Background: Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is a rare genetic disorder characterized by disabling episodes of edema that commonly affect the skin as well as the gastrointestinal tract and upper airway. Prophylactic therapy can decrease the severity and number of attacks. Long-term symptom control and rescue medication use were evaluated in patients with HAE who received subcutaneous (SC) C1-INH enrolled in an open-label extension (OLE) of the phase III COMPACT (Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy) trial, including a subgroup analysis of patients treated for ≥12 months. Methods: The OLE study evaluated patients ≥ 6 years old who had had four or more attacks over 2 consecutive months before enrollment. Patients naive for C1-INH (SC) and patients in the COMPACT rollover trial were included. The patients were randomized to receive C1-INH (SC) 40 or 60 IU/kg twice weekly for 52 weeks. U.S. patients were eligible to continue for up to 140 weeks. Results: A total of 63 patients were randomized to the U.S. Food and Drug Administration approved dose of 60 IU/kg; 24 subjects were treated for at least 12 months. For the 63 subjects, the median (range) attacks per month were 0.09 (0.0-4.0) and per year were 1.0 (0.0-48.0). Two-thirds of the patients used rescue medication fewer than once per year. For the 24 patients with ≥ 12 months of exposure, the median (range) attacks per month and per year were 0.017 (0.000-2.4) and 0.199 (0.000-28.94), respectively. Of these patients, 12 (50%) were attack free throughout the duration of the study, and 3 (12.5%) had fewer than one attack per year. Conclusion: Prophylaxis with C1-INH (SC) provided sustained reductions in attack frequency and decreased rescue medication use, with a substantial proportion of patients being attack free.

A Diagnosis of Choriocarcinoma in a Parturient Presenting With Intracranial Hemorrhage

Choriocarcinoma in a viable pregnancy is uncommon. The diagnosis can easily be missed when there is an explanation for the clinical symptoms that the cancer can mimic. We present the case of a primigravid patient whose choriocarcinoma was initially missed as a result of seemingly obvious explanations for her atypical history and disease manifestation. The patient is a Caucasian female at 30 weeks and 5 days of gestation who presented with persistent headaches and new-onset tonic-clonic seizures found on brain magnetic resonance imaging (MRI) to have a left intracranial hematoma, a 5 mm midline shift, and multiple foci of restricted diffusion. Cerebral angiogram demonstrated arteriovenous malformations (AVMs). The fetus was emergently delivered 1 week into hospitalization for non-reassuring fetal heart tracings in the setting of maternal lethargy secondary to continued AVM hemorrhage. The patient’s hospital course was complicated by four episodes of intracranial bleeding and edema requiring neurosurgical intervention. Three weeks after hospitalization she was discharged to a rehabilitation center, shortly after which placental biopsy demonstrated choriocarcinoma. MRI after readmission demonstrated extensive metastatic disease and human chorionic gonadotropin (hCG) levels were greater than 225,000 mIU/mL. Despite two additional neurosurgical procedures and extensive chemotherapy the patient died 3 months after initial presentation. Choriocarcinoma is extremely rare in viable pregnancies, but it should be considered when a parturient presents with intracranial bleeding. A high level of suspicion and serial serum hCG levels may lead to early and potentially life-saving multidrug chemotherapy. With a broader differential, earlier hCG measurement, and earlier treatment, our patient may have survived.

Gut microbiome alterations in hereditary angioedema

BackgroundHereditary angioedema (HAE) is a rare disease with wide intra- and interindividual clinical variation. There are no reliable indicators available in clinical practice to predict the onset and severity of HAE. Uncovering the changes in the gut microbiota in HAE patients may offer insight into a missing piece of the pathogenesis and help explain the clinical heterogeneity. ObjectiveExplore whether dysbiosis exists in patients with HAE and whether there are biomarkers to indicate the episodes. MethodsFecal samples and clinical data were collected from patients with C1-inhibitor–related HAE and their healthy family members. Patients were grouped on the basis of the most recent conditions of HAE episodes and major clinical manifestations. The gut microbiota was evaluated by sequencing the 16S ribosomal RNA gene and analyzed for diversity. ResultsMicrobial richness and diversity were significantly reduced among patients who had recent HAE attacks, especially for those presenting with abdominal symptoms (P = .003 and P = .048 compared with healthy controls and patients with no recent episodes, respectively). Decreased Firmicutes and increased Proteobacteria were found among the individuals with a recent episode, along with a marked increase of pathogenic bacteria on the basis of the predictive functional profiling. Dysbiosis was restored after regular use of danazol or tranexamic acid. A combined biomarker composed of Bifidobacterium, Lachnospira, Paraprevotella, Desulfovibrio, and Staphylococcus was proposed to detect the recent edema episodes. ConclusionWe reported alterations of the gut microbiome in patients with HAE and explored the possible role of bacteria in the etiology of edema episodes, which may provide new clues for the prediction of disease course, clinical treatment, and therapeutic evaluation.

Hereditary Angioedema Type I Triggered by Dental Treatment: A Case Report and Review of the Literature

Type 1 hereditary angioedema (HAE) is a rare genetic condition characterized by recurrent episodes of oedema caused by a deficiency of C1-esterase inhibitor (C1-INH). A 29-year-old male presented to the oral medicine department at Guy's Hospital, London, with lip swelling following crown preparation and impressions. Haematological investigations showed reduced levels of complement C4 (0.02 g/L; reference range 0.1–0.4 g/L) and C1-INH function was &lt;31% (reference range 85–99%). Immunology confirmed the diagnosis of type 1 HAE, with a de novo mutation. This case highlights how a detailed medical history and multidisciplinary teamwork ensure the correct diagnosis and management. CPD/Clinical Relevance: To demonstrate the various dental triggers, relevant signs and symptoms, and management options for patients diagnosed with hereditary angioedema to allow for effective decision-making in a primary dental setting.

Positioning Ozanimod in Ulcerative Colitis: Restoring Leukocyte Traffic Under Control

Positioning Ozanimod in Ulcerative Colitis: Restoring Leukocyte Traffic Under Control

M113 BLEPHAROCHALASIS: A HEREDITARY ANGIOEDEMA-MASQUERADER. RECURRENT ANGIOEDEMA IN A 12 YEAR-OLD AFRICAN AMERICAN MALE

Blepharochalasis is a rare disorder involving periocular edema classically of the upper eyelid, but has also been described in the entire periocular tissue. The resultant edema may be mistaken for allergy or hereditary angioedema. Etiology is unclear, possibly inflammatory, with some cases involving IgA deposition in the dermis, as well as perivascular inflammatory cellular infiltrates. Age of presentation ranges from just prior to puberty through the 20’s. Episodes of periocular edema tend to occur for 3-4 months for the first multiple years, then tend to space out, with acute attacks followed by quiescent phases.

Considerations for transition from subcutaneous to oral prophylaxis in the treatment of hereditary angioedema

BackgroundHereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable localized episodes of edema, which is frequently managed with long-term prophylactic medications. Until recently, long-term prophylaxis has predominantly required regular intravenous or subcutaneous administration, however the recent approval of berotralstat (Orladeyo™) offers an orally administered prophylactic which may be associated with a lower burden of treatment compared to injectable options for some patients.Case presentationThis report describes four participants in the APeX-S trial who transitioned from subcutaneously administered lanadelumab (Takhzyro®) to daily oral berotralstat for long-term HAE prophylaxis. Lanadelumab dosing continued after berotralstat commencement in all patients and was tapered before discontinuation in three of the four patients. No substantial increases in HAE attack rates were observed after the transition to berotralstat monotherapy. One patient experienced a treatment-related adverse event (dyspepsia), which was mild and self-resolving.ConclusionsAll four patients described in this case series successfully transitioned from lanadelumab to berotralstat monotherapy for long-term prophylaxis without significant complications and without the use of a complex transition protocol. The decision to transition to berotralstat monotherapy and how the transition should be achieved was discussed between patient and physician, ensuring that the comfort and perspectives of the patients were considered during the treatment transition. This report highlights the importance of individualization of HAE management plans to address both the disease and treatment burdens of HAE, and thus to provide the best possible quality of life for each patient.

S2244 Unusual Presentation of Strongyloides with Microscopic Colitis

Introduction: Strongyloides is an endemic helminth in the tropical regions of the world. It has varied presentation from asymptomatic infection to having hyper-infection syndrome and disseminated disease. We present a case of Strongyloides with microscopic colitis- whether they coexist or lead to one another. Case Description/Methods: A 57 year old male presented with multiple episodes of bilious, non-projectile vomiting and bilateral pedal edema for 15 days. He has past history for L5-S1 radiculopathy for which he was given steroids for 3 months and they were tapered off in that period. Antiemetics were started, but there was no relief. His routine blood investigations were normal except for low serum albumin. Contrast enhanced CT Abdomen was normal. Upper GI endoscopy was normal, biopsies from second part of duodenum was taken. Colonoscopy was done;the mucosa was normal and segmental biopsies were taken. Stool examination and duodenal mucosa showed presence of the larva of Strongyloides. Histopathoplogy of colonic mucosa showed features of microscopic colitis; lamina propria in the ileum and caecum showed inflammatory infiltrate and lymphoid aggregates with eosinophils. Transverse colon stroma showed mixed inflammatory infiltrate with many eosinophils and occasional lymphoid aggregates. Oral ivermectin was started and given for 5 days. Along with anti-helminthic, oral budesonide was also given for microscopic colitis. His symptoms improved and was doing well on follow up. Discussion: S.stercorails has the unique ability to complete its life cycle within the host through an asexual autoinfective cycle, allowing infection to persist in the host indefinitely. Immunocompromised state can precipitate hyperinfection syndrome. Hallmark of hyperinfection syndrome is the increase in the larvae in the stool or the sputum leading to gastrointestinal and pulmonary symptoms. GI symptoms include abdominal pain, nausea, diarrhoea and rarely intestinal obstruction and GI hemorrhage. Our patient didn’t develop any of these symptoms while on steroids. On the other hand, microscopic colitis presents with chronic diarrhoea. These symptoms were also not present. Our patient had symptoms due to increased larval load leading to repeated episodes of vomiting. There is scant literature if Strongyloides leads to microscopic colitis. Bacterial infection leading to microscopic colitis is known but parasitic cause is not known yet.Figure 1.: A: Normal stomach with food residue. B: Normal appearing mucosa of the ascending colon. C: Homogeneous eosinophilic deposits of amyloid in submucosal blood vessels of the small bowel (conventional haematoxylin and eosin-stained section 20x) D: Reddish-orange appearance of amyloid protein deposit in submucosal blood vessels of small bowel (congo red-stained section 20x).

Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America

BackgroundLipoprotein glomerulopathy (LPG) is a rare autosomal dominant disease caused by mutations in APOE, the gene which encodes apolipoprotein E. LPG mainly affects Asian individuals, however occasional cases have also been described in Americans and Europeans. Herein we report two unrelated Brazilian patients with LPG in whom genetic analyses revealed the APOE-Osaka/Kurashiki variant.Case presentation - case 1A 29-year-old Caucasian male sought medical attention with complaints of face swelling and foamy urine for the last 3 months. He denied a family history of kidney disease, consanguinity, or Asian ancestry. His tests showed proteinuria of 12.5 g/24 h, hematuria, serum creatinine 0.94 mg/dL, albumin 2.3 g/dl, total cholesterol 284 mg/dL, LDL 200 mg/dL, triglycerides 175 mg/dL, and negative screening for secondary causes of glomerulopathy. A kidney biopsy revealed intraluminal, laminated deposits of hyaline material in glomerular capillaries consistent with lipoprotein thrombi. These findings were confirmed by electron microscopy, establishing the diagnosis of LPG. His apolipoprotein E serum level was 72 mg/dL and genetic analysis revealed the APOE pathogenic variant c.527G > C, p.Arg176Pro in heterozygosis, known as the Osaka/Kurashiki mutation and positioned nearby the LDL receptor binding site.Case 2A 34-year-old Caucasian man sought medical assessment for renal dysfunction and hypertension. He reported intermittent episodes of lower-limb edema for 3 years and a family history of kidney disease, but denied Asian ancestry. Laboratorial tests showed BUN 99 mg/dL, creatinine 10.7 mg/dL, total cholesterol 155 mg/dL, LDL 79 mg/dL, triglycerides 277 mg/dL, albumin 3.1 g/dL, proteinuria 2.7 g/24 h, and negative screening for secondary causes of glomerulopathy. His kidney biopsy was consistent with advanced chronic nephropathy secondary to LPG. A genetic analysis also revealed the Osaka/Kurashiki variant. He was transplanted a year ago, displaying no signs of disease relapse.ConclusionWe report two unrelated cases of Brazilian patients with a diagnosis of lipoprotein glomerulopathy whose genetic assessment identified the APOE-Osaka/Kurashiki pathogenic variant, previously only described in eastern Asians. While this is the second report of LPG in Latin America, the identification of two unrelated cases by our medical team raises the possibility that LPG may be less rare in this part of the world than currently thought, and should definitely be considered when nephrotic syndrome is associated with suggestive kidney biopsy findings.

Berotralstat (BCX7353) is a novel oral prophylactic treatment for hereditary angioedema: Review of phase II and III studies.

Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable and potentially life-threatening episodes of swelling in various parts of the body. These attacks can be painful and debilitating, and affect a patient's quality of life. Every patient who experiences an attack should be treated with on-demand medication to mitigate attack severity and duration. Many patients with HAE also receive long-term prophylaxis to reduce the frequency and severity of edema episodes. Although long-term prophylaxis reduces the disease burden for patients with HAE, available intravenous and subcutaneous treatments are accompanied by a significant treatment burden because of the logistical, emotional, and physical challenges posed by their long-term parenteral nature. Androgens are an effective oral prophylactic treatment; however, they are associated with significant adverse events and are not suitable for all patients. Thus, the HAE community has expressed interest in the development of alternative oral prophylactic therapies for preventing HAE attacks. Objective: Here, we review the phase II and III clinical data of berotralstat (BCX7353), which was approved by the U.S. Food and Drug Administration in December 2020. Results: Berotralstat is an oral, second-generation, synthetic, small-molecule plasma kallikrein inhibitor taken once daily for the prevention of HAE attacks in patients ages ≥ 12 years. Results from the APeX studies (APeX-1 NCT02870972, APeX-2 NCT03485911, APeX-S NCT03472040, APex-J NCT03873116) demonstrated the efficacy of berotralstat as long-term prophylaxis for patients with HAE, which showed a reduction in the attack rate and on-demand medication usage. Berotralstat was well tolerated, and gastrointestinal treatment-emergent adverse events were generally mild and self-limited. Conclusion: Oral berotralstat is an effective and safe long-term prophylactic treatment for patients with HAE that will provide patients unable to tolerate parenteral therapies with the option of disease control. Berotralstat may be associated with reduced treatment burden compared with injectable therapies, highlighting the importance of patient preference with regard to the administration route of their HAE prophylactic treatment.

P-236 Combined squamous cell and neuroendocrine carcinoma of the larynx. A case report

Presented by: Javier Padilla-Cabello (jpadillacabello@gmail.com) Introduction A 67-year-old male patient, smoker of more than a pack a day since childhood, presented to the emergency department with a right cervical tumor and dysphagia of twoweeks' evolution. On examination, cervical palpation revealed an adenopathy in the right area IIa of about 5 cm in diameter, stony and adherent to deep planes. Fibrolaryngoscopy showed a lesion on the right laryngeal surface of the epiglottis and a leukoplakia in the right lateral glossoepiglottic fold. Therefore, it was decided to perform transoral laryngeal microsurgery to take biopsies and request CT for extension study. Materials and Methods The samples taken in the operating room and the CT scan showed that it was an epidermoid carcinoma of the supraglottis stage cT1N2BM0. It was decided to perform a right hemiepiglottectomy with extension to the right lateral glossoepiglottic fold by transoral laser surgery together with bilateral functional cervical emptying. The patient required a tracheotomy due to an episode of severe post-surgical laryngeal edema and the cannula had to be maintained, together with a gastrostomy, because the patient subsequently developed dysphagia with aspiration of secretions and food. Results Histopathological analysis showed that it was a combined tumor: on the one hand a poorly differentiated epiglottic neuroendocrine carcinoma (NEC) (CK-20 +, S100 +, Ki67 90%) with cervical metastasis and on the other hand a supraglottic squamous cell carcinoma in the right glossoepiglottic fold with one cervical metastasis (pT1N1). The case was presented to the oncology committee and it was decided to complete treatment with chemoradiotherapy. Chemotherapy was administered with a reduced dose of carboplatin (AUC = 3) and etoposide. Despite treatment, local cervical tumor progression was observed in the control CT scan and the patient finally died a few weeks later due to COVID19. Conclusions NEC of the larynx are very rare and aggressive, so an accurate histopathologic diagnosis is essential for early treatment. Their most frequent location is the supraglottis and the clinical presentation of the patient is a mild odynophagia or a cervical mass. Very few associated cases of synchronous laryngeal squamous cell carcinoma have been described. Treatment of NEC is based on chemoradiotherapy with a survival rate of less than 5% at 5 years.

In Reply: Risk of Brain Herniation After Craniotomy With Preoperative Lumbar Spinal Drainage: A Single-Surgeon Experience of 365 Patients Among 3000 Major Cranial Cases.

To the Editor: We sincerely appreciate the kind words of the colleagues1 who deserve our respect for their work and contributions. We rarely use diuretics for brain relaxation, as cerebrospinal fluid drainage obviates the need for this class of agents. In addition, we do not believe that the mechanism of edema among the patients described in our paper2 was related to a lack of use of diuretics because those edema episodes were localized. We look forward to the upcoming results of our colleagues’ studies. Funding This study did not receive any funding or financial support. Disclosures The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

REVIEW OF THE FUNCTION OF SEMA3A IN LYMPHATIC VESSEL MATURATION AND ITS POTENTIAL AS A CANDIDATE GENE FOR LYMPHEDEMA: ANALYSIS OF THREE FAMILIES WITH RARE CAUSATIVE VARIANTS

SEMA3A is a semaphorin involved in cell signaling with PlexinA1 and Neuropilin-1 (NRP1) receptors and it is responsible for recruiting dendritic cells into lymphatics. Mutations in the SEMA3A gene result in abnormalities in lymphatic vessel development and maturation. We investigated the association of SEMA3A variants detected in lymphedema patients with lymphatic maturation and lymphatic system malfunction. First, we used NGS technology to sequence the SEMA3A gene in 235 lymphedema patients who carry wild type alleles for known lymphedema genes. We detected three different missense variants in three families. Bioinformatic results showed that some protein interactions could be altered by these variants. Other unaffected family members of the probands also reported different episodes of subclinical edema. We then evaluated the importance of the SEMA3A gene in the formation and maturation of lymphatic vessels. Our results determined that SEMA3A variants segregate in families with lymphatic system malformations and recommend the inclusion of SEMA3A in the gene panel for testing of patients with lymphedema.

Clinical presentation of hereditary angioedema.

Hereditary angioedema (HAE) is a rare, autosomal dominant disease caused by a deficiency in the C1-inhibitor protein. It is characterized by recurrent episodes of nonpruritic, nonpitting, subcutaneous or submucosal edema that typically involves the extremities or the gastrointestinal tract. However, the genitourinary tract, face, oropharynx, and/or larynx may be affected as well. Symptoms often begin in childhood, worsen at puberty, and persist throughout life, with unpredictable severity. Patients who are untreated may have frequent attacks, with intervals that can range from every few days to rare episodes. Minor trauma and stress are frequent precipitants of swelling episodes, but many attacks occur without clear triggers. HAE attacks may be preceded by a prodrome and/or be accompanied by erythema marginatum. The swelling typically worsens over the first 24 hours, before gradually subsiding over the subsequent 48 to 72 hours. Although oropharyngeal swelling is less frequent, more than half of patients have had at least one episode of laryngeal angioedema during their lifetime. Attacks may start in one location and spread to another before resolving. HAE attacks that involve the abdomen or oropharynx have been associated with significant morbidity and mortality. Abdominal attacks can cause severe abdominal pain, nausea, and vomiting. Bowel sounds are often diminished or silent, and guarding and rebound tenderness may be present on physical examination. These findings may lead to unnecessary abdominal imaging and procedures. Fluid shifts into the interstitial space or peritoneal cavity can cause clinically significant hypotension. Laryngeal edema poses the greatest risk for patients with HAE. Although prompt diagnosis and treatment improves outcomes, the variable presentation of HAE can make it difficult to diagnose.