Severe epidermolysis bullosa acquisita in a patient with graft-versus-host disease: causal or coincidental?

Graft-versus-host disease (GvHD) is common after haematopoietic cell transplantation (HCT). Mucocutaneous manifestations are variable and may simulate autoimmune bullous dermatoses. However, the association of GvHD with autoimmune disorders, including bullous dermatoses, is also well recognized. We describe a patient with GvHD in whom severe and relapsing epidermolysis bullosa acquisita (EBA) was diagnosed 3 years after transplant and propose a causal association with GvHD. A 66-year-old woman developed GvHD following allogeneic HCT for acute myeloid leukaemia in 2016. This affected her gastrointestinal tract and skin but improved with oral corticosteroids and ciclosporin. In 2019 she presented with a widespread rash consisting of large, tense, haemorrhagic blisters. Histological features were in keeping with EBA. Direct immunofluorescence was also consistent with EBA, demonstrating linear positivity for IgG and C3 confined to the blister base, as was detection of collagen VII antibodies on indirect immunofluorescence. She was admitted and treated with high-dose oral steroids, ciclosporin and intravenous immunoglobulin (IVIg) with eventual resolution of blistering. Although further IVIg administration was planned as an outpatient, this coincided with the start of the COVID-19 pandemic and she elected not to attend and also stopped all medication. Despite this, her EBA remained quiescent until September 2021 when she was readmitted with a severe deterioration in blistering and significant dysphagia due to an oesophageal stricture, with a weight of 31.7 kg. Once again, she responded rapidly to oral prednisolone and IVIg. Dapsone was considered but precluded by G6PD deficiency and there were clinical and adherence concerns about using mycophenolate mofetil. Upon discharge she was again nonadherent to medication and failed to attend for planned IVIg. She flared and was admitted for a third time in December 2021, requiring gastrostomy for nutritional support;her weight at this time was 26.4 kg. Her EBA is currently well controlled on prednisolone and IVIg. EBA is a rare, acquired blistering disorder secondary to autoantibodies targeting type VII collagen. Previous studies have found circulating basement membrane zone (BMZ) antibodies in 24% of chronic GvHD patients, possibly generated in response to chronic BMZ damage (Hofmann SC, Kopp G, Gall C et al. Basement membrane antibodies in sera of haematopoietic cell recipients are associated with graft-versushost disease. J Eur Acad Dermatol Venereol 2010;24: 587-94). Corresponding clinical manifestations are rare, with bullous pemphigoid the most frequently reported. EBA is much less common with four previously reported cases [Brassat S, Fleury J, Camus M, et al. (Epidermolysa bullosa acquisita and graftversus- host disease). Ann Dermatol Venereol 2014;141: 369-73 (in French)]. As a fifth case of EBA, our patient provides further evidence of a likely pathophysiological relationship between GvHD and autoimmune subepidermal bullous dermatoses, and highlights the significant challenges of managing these vulnerable patient groups during the COVID-19 pandemic.

Adverse Events of BNT162b2 (Pfizer) COVID-19 Vaccine in Children Aged 12 to 17 Years in Thailand

Background: The coronavirus disease 2019 (COVID-19) has been sabotaging the world over the last two years and vaccine is one of the key solutions. However, the concerns over its side effects can cause vaccine refusal, subsequently affecting many countries' education system recovery plans. Objective(s): To actively evaluate adverse effects and their severity following COVID-19 immunization among schoolchildren aged 12 to 17 years, to support parents' decision-making. Material(s) and Method(s): The present study was an observational study whereby a Google-form survey on Pfizer COVID-19 vaccine adverse effects (CVAE) was responded between January and April 2022 by 537 participants. Descriptive statistics were used to analyze basic characteristics. Chi-square tests were performed for comparative analyses between junior (aged 12 to 15 years) versus senior (aged 16 to 17 years) high school students, and McNemar's test for the first dose versus second dose groups analysis with a significance level set at p-value less than 0.05. Result(s): At least one CVAE was reported in 93.85% of the included participants, albeit mostly mild. The most common symptom as a local event was tenderness at the puncture site (82.50%), whereas systemic events were predominated by myalgia (74.67%). The second dose was associated with increased frequency and severity of adverse effects compared to the first dose (p<0.001). The older age group had significantly more side effects compared to the younger group (p<0.05). Conclusion(s): The high incidence of CVAEs in schoolchildren was predominated by mild symptoms, with the second dose and older group associated with increased frequency of symptoms. The predominance of mild symptoms found in the present study may help reduce the concerns of parents over CVAEs, ultimately accelerating vaccine coverage in the children group, which is still a gap in vaccine administration.Copyright © 2023 JOURNAL OF THE MEDICAL ASSOCIATION OF THAILAND.

An Old Mobbing Story and Covid-19

Innovative medical education greatly relies on lifelong learning with universal standards in research, for generating novel knowledge for improvement maximum patient care. The other side of innovative medical education relies on success of development of novel ideas, perspective;skill building, future career objectives. Leaders have curious roles in the research assistant education. In the current century, both technology and education raced forward in many countries. Mobbing and bullying is an important problem in all fields, every sphere of life in workplaces. Unethical behavior must not take place in universities because universities are the centers of learning, and best academic teaching in ethical standards. Bullying may damage every individual in every academic degree and effect academic performance. In this paper I will discuss a mobbing case which is done to a young academician in many years ago, which is not most frequently observed type. However, such bullying behaviors may increase due to COVID-19 pandemic. Because COVID-19 pandemic may cause various problems in social groups difficulties, anxiety, and economic challenges, problems. Nowadays everybody is experiencing worry, uncertainty, anxiety, fear of economic problems, fear of dying. COVID-19 pandemic has created some unexpected problems to everybody however, academic researchers have additional worries and fears such as;the expiration time of chemicals, problems on chemicals are not imported from abroad on time also difficulties of knockout or transgenic experimental animals cannot be imported from abroad on time, and all these problems cause fear of unsuccessful experimental results, spending extra time. All these anxieties may cause arouse increasing unstable friendships and mobbing possibilities. The COVID-19 disease takes our future and experimental plans to waste basket and change everything including friendship.

G6PD Insufficiency, Redox Equilibrium, and Viral Infections: Insinuations for SARS-CoV-2

The COVID-19 epidemic has inflicted damage on more than 4 crore 50 lakh people worldwide, resulting in over 10 lakh deaths. Infestation with the pathogenic SARS-CoV-2 virus leads to excessive inflammation and a cytokine storm, which leads to cell rupture due to a redox imbalance. The severe type of pneumonia caused by the human coronavirus (hCoV)-SARS-CoV-2 has caused heavy casualties, especially among the old age and those with comorbid illnesses all-inclusive of their age. The high mortality in African-American males, in general, raises the concern for a possible X-linked modulated process that could affect the viral pathogenesis and the immune system. When exposed to oxidants or infection, patients who lack the enzyme Glucose-6-Phosphate Dehydrogenase (G6PD) may have a haemolysis phenomenon. People with a G6PD deficiency are more prone to take up a virus than people with normal G6PD. G6PD deficiency causes a distinct immunological reaction to viral infections in people. G6PD insufficiency appears to be a predisposing factor for COVID-19 infection. Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD) is known to suppress the antioxidant system and is likely to aggravate severity of COVID-19 infection, which results in a pro-oxidant response leading to higher morbidity and mortality.

REFRACTORY HYPOXEMIA: A CASE OF DAPSONE-INDUCED METHEMOGLOBINEMIA IN A PATIENT WITH COVID-19

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Methemoglobinemia is an increase in methemoglobin (mHb) level characterized by functional anemia and tissue hypoxia. It can be caused by congenital enzymes deficiencies, but it is usually acquired. Dapsone, an oxidizing agent, is a medication commonly associated with acquired methemoglobinemia (1). We describe the diagnosis and management of a COVID-19 patient with acquired methemoglobinemia due to Dapsone. CASE PRESENTATION: 84-year-old female with history of MPO-ANCA vasculitis with renal involvement, CKD4 and anemia of chronic disease presented with shortness of breath, lethargy and weakness. Initially, the patient was saturating (SpO2) 80% on room air and was placed on 4L nasal cannula (NC) with improvement to 92%. CT of the chest showed b/l GGOs consistent with atypical pneumonia and patient tested positive for COVID-19. About 4 months prior, she had received 2 doses of Rituximab and on high steroid therapy that was tapered to 5mg of prednisone daily. She has been on Trimethoprim/Sulfamethoxazole for PJP prophylaxis, but due to hyperkalemia the medication was stopped. After confirming no G6PD deficiency, she was started on Dapsone 100mg daily. During hospitalization, she was given dexamethasone 6 mg daily and Dapsone was continued. On hospital stay day 6, a rapid response was called after oxygen dropped to 78% while walking on 6L NC. She was placed on high flow NC 100% and SpO2 went up to 90%. An arterial blood gas (ABG) was then obtained showing pO2 of 334, oxyhemoglobin (oxyHb) of 83 and mHb of 17.4. The SpO2-PaO2 gap and elevated mHb lead to the diagnosis of Dapsone-induced methemoglobinemia. Dapsone was discontinued. Patient received a one-time dose of 1mg/kg IV of methylene blue. One hour later her dyspnea had improved and was on 3L NC. Repeat ABG showed improvement of oxyHb (98) and decreased mHb (2.2). DISCUSSION: Physiologically, mHb is less than 1% of total Hb (1) and occurs when the iron in the porphyrin group of heme is oxidized from ferrous to the ferric form (2). Ferric heme binds oxygen irreversibly causing a left shift of the oxygen-hemoglobin dissociation curve. Clinical presentation tends to correlate with mHb levels, and it varies from being asymptomatic to fatigue, dyspnea, confusion, seizure, cyanosis resistant to oxygen therapy (mHb > 15%) and death. Methylene blue is safe and can be consider when mHb level is greater than 10 to 20% (2). Methylene blue was administer to our patient given the presence of COVID (leaving patient more susceptible to medication-induced methemoglobinemia (3)) and chronic anemia which made her less likely to tolerate state of reduced oxygen delivery. CONCLUSIONS: The diagnosis of methemoglobinemia is a rare cause of hypoxemia that is often overlooked. In patients with risk factors (COVID, medication exposure) a high index of suspicion is needed when interpreting an ABG (SpO2-PaO2 gap) for correct diagnosis and appropriate treatment. Reference #1: Toker, Ibrahim, et al. "Methemoglobinemia Caused by Dapsone Overdose: Which Treatment Is Best?” Turkish Journal of Emergency Medicine, vol. 15, no. 4, Dec. 2015, pp. 182–184, 10.1016/j.tjem.2014.09.002. Accessed 31 Aug. 2020. Reference #2: Cortazzo JA, Lichtman AD. Methemoglobinemia: a review and recommendations for management. J Cardiothorac Vasc Anesth. 2014 Aug;28(4):1043-7. doi: 10.1053/j.jvca.2013.02.005. Epub 2013 Aug 13. PMID: 23953868. Reference #3: Naymagon, Leonard, et al. "The Emergence of Methemoglobinemia amidst the COVID -19 Pandemic.” American Journal of Hematology, vol. 95, no. 8, 3 June 2020, 10.1002/ajh.25868. Accessed 3 Mar. 2021. DISCLOSURES: No relevant relationships by Mileydis Alonso No relevant relationships by Samantha Gillenwater No relevant relationships by Christine Girard No relevant relationships by Sikandar Khan No relevant relationships by Jose Rivera No relevant relationships by Frederick Ross

RARE CASE OF G6PD DEFICIENCY DIAGNOSED IN AN ADULT AFTER COVID-19 INFECTION

SESSION TITLE: Genetic and Developmental Disorders Case Report Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Glucose-6-phosphate-dehydrogenase (G6PD) deficiency is one of the more common hematologic disorders. Many individuals are asymptomatic until a triggering event. Events that lead to hemolysis in the setting of G6PD include certain medications, infections, and specific foods. We discuss a case of G6PD deficiency diagnosed in a hospitalized adult with COVID infection. CASE PRESENTATION: A 41 year old male presented to the hospital with altered mental status. On admission he was found to be in diabetic ketoacidosis and was COVID positive. He was admitted to the ICU and his acidosis was corrected with insulin. He did not require intubation but was treated with steroids, remdesivir, and supplemental oxygen for his COVID pneumonia. His hospitalization was complicated by hemolytic anemia. Testing for autoimmune hemolytic anemia and HIT (heparin induced thrombocytopenia) were negative. Genetic testing for G6PD deficiency came back positive. The patient was discharged and referred to hematology for follow up. DISCUSSION: Interestingly, our patient was asymptomatic prior to his COVID infection. It is likely that the stress from his COVID infection triggered worsening hemolysis. G6PD can be worsened with specific medications or foods but we cannot exclude infection. The inflammatory response secondary to COVID is the probable cause for the patient's hemolytic anemia presentation and subsequent G6PD deficiency diagnosis. CONCLUSIONS: G6PD deficiency should be included in the differential diagnosis for patients presenting with COVID infection and labs consistent with hemolytic anemia. Reference #1: Buinitskaya Y, Gurinovich R, Wlodaver CG, Kastsiuchenka S. Centrality of G6PD in COVID-19: The Biochemical Rationale and Clinical Implications. Front Med (Lausanne). 2020;7:584112. Published 2020 Oct 22. doi:10.3389/fmed.2020.584112 DISCLOSURES: No relevant relationships by Sarin Atam No relevant relationships by Kathleen Coppola No relevant relationships by Malik Muhammad Uzair Khan No relevant relationships by Mackenzie Kramer No relevant relationships by Rameesha Mehreen No relevant relationships by Stephanie Tzarnas No relevant relationships by Laura Walters

The Possible Role of Glucose-6-Phosphate Dehydrogenase in the SARS-CoV-2 Infection.

Glucose-6-phosphate dehydrogenase (G6PD) is the second rate-limiting enzyme of the pentose phosphate pathway. This enzyme is present in the cytoplasm of all mammalian cells, and its activity is essential for an adequate functioning of the antioxidant system and for the response of innate immunity. It is responsible for the production of nicotinamide adenine dinucleotide phosphate (NADPH), the first redox equivalent, in the pentose phosphate pathway. Viral infections such as SARS-CoV-2 may induce the Warburg effect with an increase in anaerobic glycolysis and production of lactate. This condition ensures the success of viral replication and production of the virion. Therefore, the activity of G6PD may be increased in COVID-19 patients raising the level of the NADPH, which is needed for the enzymatic and non-enzymatic antioxidant systems that counteract the oxidative stress caused by the cytokine storm. G6PD deficiency affects approximately 350-400 million people worldwide; therefore, it is one of the most prevalent diseases related to enzymatic deficiency worldwide. In G6PD-deficient patients exposed to SARS-CoV-2, the amount of NADPH is reduced, increasing the susceptibility for viral infection. There is loss of the redox homeostasis in them, resulting in severe pneumonia and fatal outcomes.

FATE OF THE FACE MASKS IN THE ENVIRONMENT AFFECT HUMAN AND WILDLIFE: TONS OF FACE MASKS ARE NEW SOURCE FOR THE ENDOCRINE DISRUPTING CHEMICALS

COVID-19 pandemic has become a major public health problem affecting the lives of billions of people worldwide. There is an effective vaccine treatment for the coronavirus infection, but self-isolation and self-protection are the important options to stop the spread of the virus. Usage of the surgical and other face masks are must during COVID-19 pandemic and millions of used masks are accumulating as trash in the environment every day worldwide. Face masks are made of plastic materials mainly polypropylene which is categorized as endocrine disruptor affecting both humans and wildlife. Contamination of face masks to soil, oceans, sea and air may have increased the amount of microplastics concentration and these microplastics from the face masks may have various negative effects on the environment. However, what needs to be done to protect the environment and public health is to dispose of these masks in a very convenient way. Therefore, accurate elimination and collection of used face masks from the environment should be considered to protect our world. Nowadays there are different types of vaccines are in the protecting against death, hospitalization and seriousness of the COVID-19 infection but using face masks are simple, seems safe and effective way from protection against the disease. In this review, we aimed to draw attention to the fact that a using a face mask is very important for staying safe, but they may cause environmental pollution and have adverse effects on directly health and environment.

Occurrence of Methemoglobinemia due to COVID-19: A Case Report.

Methemoglobinemia (MetHb) is a rare, life-threatening condition that occurs when the body is exposed to oxidative stress. It is typically corrected through the glucose-6-phosphate dehydrogenase (G6PD)-dependent shunt. G6PD deficiency is the most common enzymatic deficiency worldwide. This genetic disorder makes patients susceptible to oxidative stress and reduces the expected life span of erythrocytes (red blood cells (RBCs)) among other cells. G6PD deficiency is asymptomatic in most cases unless exogenous stressors are introduced, whether they are dietary, iatrogenic, or infections, such as the highly transmissible serotype of coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report a case of an 11-year-old male with known insulin-dependent diabetes mellitus (IDDM) and glucose-6-phosphate dehydrogenase (G6PD) deficiency, who was found to develop methemoglobinemia after being infected by the SARS-CoV-2 virus. The direct effects of COVID-19 on children were reported to be lower than on adults. However, the effects of COVID-19 on children with comorbidities, such as G6PD deficiency in our patient, are understood only to a minimal extent. Moreover, identifying cases of G6PD deficiency prior to initiating treatment with methylene blue, hydroxychloroquine (HCQ), or other contraindicated agents is essential to prevent further deterioration in symptoms.

eP520: Screening results in 186 any-health-status adults in primary care clinics receiving clinical NGS for 431 health risk and recessive genes

Introduction: The ACMG has recommended returning clinically relevant results for certain genes when identified in research or as secondary findings in diagnostic testing. Research studies have shown that genomic population screening detects patients with previously unrecognized and often actionable health risks or genetic conditions, with acceptably low levels of harm. Cascade testing of relatives at risk is enabled. Screening for recessive disorder carrier status with gene sequencing panels is common in clinical practice. Preventative screenings routinely occur in primary care settings. The cost of reliably sequencing of many genes in a clinically reliable fashion is approaching levels where offering genomic screening tests may be contemplated for entire populations, and the results used for preventative health purposes, including clinical correlation, early screening, and education. In anticipation of universal genome sequence-based screening, integrated with existing health risk screenings, we piloted a novel implementation of clinical genomic population screening in primary care, mostly family medicine clinics. Screening involved clinical sequencing and reporting of 431 genes where variants are associated with personal health risks or recessive disease carrier status. Methods: Interested primary care providers (PCPs) in two Family Medicine practice systems were invited to participate and given onboarding education. Adult patients with any health status were introduced to The Genomic DNA Test and provided test information by their PCPs in the context of preventative health assessment. Patient education materials included paper, online, and video information, a ‘hotline,’ and optional free genetic counseling. Patients completing a bespoke, health system-approved, written clinical consent provided blood or occasionally saliva samples that were NGS sequenced according to validated procedures in a commercial CLIA-certified genetic testing laboratory. Laboratory reports were returned to the PCP and patient after a local genetics professional added a 1-to-3-page messaging document, the Genomic Medicine Action Plan (GMAP). The PDF-format reports and GMAP were placed in the patient’s electronic health record. Only pathogenic (P) and likely pathogenic (LP) variants were reported. Variant classification was according to Sherloc, the performing laboratory’s system. Patients or providers could request free post-test genetic counseling locally, and the performing lab offered free family member testing and limited-cost partner testing for health risk panel genes and recessive disorder panel genes, respectively. Patients with health risk results were defined as being heterozygous for a P/LP variant for a dominant condition or for a recessive condition where some heterozygotes are symptomatic or co-dominant, hemizygous for a P/LP variant for an X-linked recessive condition, or bi-allelic and plausibly in trans for an autosomal (or X-linked in a female) recessive condition. Many such conditions that are common have reduced or low penetrance, and were characterized as increased risk compared to those not having those variants. When increased risk was identified, the GMAP recommended appropriate medical responses and/or patient education. As part of quality assessment of the pilot, the frequencies of reported results and certain events are monitored. Results: Between November 2019 and October 2021, 186 patients with a median age of 58 years were tested by 20 PCPs at no cost to patients or insurance. Testing volumes declined during the COVID-19 pandemic and when other health system events made high demands on PCPs and their staff. Only 13.3% of patients had no reportable variants in any of the 431 genes. Eighty point nine percent were carriers for at least one recessive disease. The most common recessive genes showing carrier status were HFE, SERPINA1, GALT, CFTR, BTD, F5, DHCR7, PC, GAA, GJB2, PMM2, PAH, and PKHD1. Twenty-six percent had at least one potential health risk result identified, 20% if the common thrombophilias are excluded. The most common category was hereditary cancer risk (7.5%), followed by F5, F2, and SERPINC1 thrombophilia variants (6.5%), hereditary hemochromatosis 1 (HFE) (4.3%), cardiovascular disorders, mostly cardiomyopathies (3.8%), alpha-1-antitrypsin deficiency or other pulmonary disorder (3.8%), familial Mediterranean fever heterozygotes (1.6%), G6PD deficiency (1.1%), and lipid disorder (0.5%). Two patients had health risks in two areas, and two in three areas. Interestingly, BRCA1 and BRCA2 variants were only identified in males. Thirteen patients, about 7%, had an amended report issued during the period. This happened when an unreported variant of uncertain significance was reclassified as LP or P, or when LP became P, and the performing laboratory issued an amended report. Surprisingly few patients took advantage of the free genetic counseling. No patient adverse events were reported by the participating PCPs despite ongoing outreach, nor by patients. Conclusion: Genomic population health screening can be successfully implemented in primary care settings with use of limited but essential genetic professional assistance, after careful planning and input from other medical specialties. A significant proportion of adults not selected for health status harbors germline genetic variants associated with increased health risk. In the absence of a culture where routine genomic screening is expected and where patient genomic competency is high, PCP capacity limits are a barrier to universality. Inclusion of genes for both health risk results with variable degrees of penetrance and for recessive carrier status, and multiple simultaneous results, dictates careful messaging of the implications, while doing so in a primary care setting begs a concise and efficient process. Rates of carrier detection were in-line with predictions based on general population frequencies. Rates of health risk detections were higher than earlier research programs because a larger number of genes with a much broader scope of health risk was included, including disorders with low penetrance yet meaningful clinical relevance and carefully-designed care pathways meant to optimize care while avoiding unnecessary additional testing. We conclude that genomic population health screening of primary care patients where large numbers of genes are clinically sequenced is feasible in a real-world health system, and that value exists for some tested patients now. Research to overcome certain technical limitations of current clinical genomic testing methods and to better stratify risk level in the context of incomplete penetrance should enhance the value of universally-offered genomic population health screening in the future.

eP455: Fetal ultrasound presentation and neonatal diagnosis of Freeman-Sheldon syndrome in son of previously undiagnosed adult male

Background: Freeman-Sheldon syndrome [distal arthrogryposis type 2A (OMIM #193700), DA2A, Freeman-Burian syndrome] is a rare autosomal dominant multiple pterygium syndrome caused by alterations in MYH3. The phenotypic features, particularly of the face, are distinct and easily recognizable, and the diagnosis can be confirmed with molecular gene analysis. Fetal ultrasound imaging may provide important diagnostic clues to facilitate the diagnostic process. Informed consent and parental permission were provided by the parents. Case presentation: The infant’s mother presented for a Maternal Fetal Medicine genetic counseling telehealth appointment (due to COVID-19 pandemic restrictions) as a G7P2132, 32-year old female who had insulin-dependent diabetes and thrombocytosis. Her partner was a 24-year old male with a history of hearing loss, a V-shaped palate, and a lower lip cleft. Gestational age was 14 4/7 weeks and the indications were: increased nuchal translucency, paternal complex medical history, maternal G6PD heterozygote, and recurrent pregnancy loss. During the genetic counseling session, the following were addressed: 1) Maternal heterozygote status for G6PD indicated that if the fetus was male, there was a 50% chance he would be affected with G6PD-deficiency;2) Increased nuchal translucency on fetal ultrasound (US) with measurement at 98th percentile is associated with an increased risk of chromosomal abnormalities, microdeletion/duplications, and Noonan syndrome. The patient reportedly had low risk cell-free DNA but results were not available to the counselor at the time of consult. The option for additional genetic screening and diagnostic testing was declined;3) Three first trimester pregnancy losses with the father of this baby (FOB) were addressed, and parents deferred chromosome analyses at the time;4) Mother shared FOB’s complex history of bilateral sensorineural hearing loss, V-shaped cleft palate, lower lip cleft, and micrognathia. However, father was not present during the telehealth encounter. Mother was counseled regarding the possibility of an autosomal dominant condition with the potential risk to the pregnancy of up to 50%. It was recommended that the FOB have a clinical genetics evaluation, which could potentially provide a specific diagnosis and inform recurrence risk and management guidance. Follow-up MFM genetic counseling telephone visit occurred with the mother at 31 6/7 weeks gestation due to multiple congenital anomalies evident on fetal ultrasound. A 25 week fetal ultrasound revealed hypotelorism and a thickened nuchal translucency. A repeat study at 29 weeks revealed a V-shaped palate with a possible cleft, micrognathia, and midline mandibular cleft. FOB’s history was revisited. It was determined that he had 3 previous “no shows” to Genetics clinic appointments and did not pursue evaluation after the last counseling appointment. Again, it was emphasized that in order to best make a diagnosis for the family, an affected person would need to undergo a thorough evaluation, including medical and family history review, physical examination, and any indicated genetic testing. The parents were comfortable with the likelihood that the baby had the same condition as the father, but variable expressivity and broad range pf phenotypic presentation were explained. Recommendations for postnatal evaluation of the infant and pertinent genetic testing were provided. Consultative Genetics evaluation of the infant at 2 days of age revealed a short, broad forehead with supraorbital fullness leading to a horizontal brow indentation;mask-like facial appearance;hypotelorism;very deep set eyes with blepharophimosis;deep, creased nasal bridge;small, upturned nose with hypoplastic alae and narrow nares;microstomia with pursed lips;glossoptosis;micrognathia;2 deep vertical chin creases;short neck with excess nuchal skin;inverted and wide spaced nipples;clenched hands with 5th digits overlying 4th and 2nd overlying 3rd, bilaterally;bilateral vertical talus;2nd toes longer and overlying rd toes;clinodactyly of 4th and 5th toes bilaterally;and deep gluteal crease with no visible sinus. There were no evident contractures. The father has a complex history with no medical assessments prior to age 18. He reported that he did “not look like anyone else” in his family. He has a diagnosis of autistic spectrum disorder, a submucous cleft, vision issues, hearing loss necessitating a hearing aid on the left, and a history of cholesteatomas and of mastoidectomy. On brief examination, he had a mask-like face, blepharophimosis, left microphthalmia, left esotropia, narrowing of his midface, deep vertical crease on the mandibular region, microstomia, broad great toes, single flexor creases on the thumbs, and contracture of right thumb. Maxillofacial CT of the infant revealed hypoplastic mandibular body, ramus, and condyles bilaterally with micrognathia and retrognathia;hypoplastic maxilla bilaterally;and enophthalmos with retracted appearance of globes in the bony orbits bilaterally. Multiple facial bone abnormalities were seen, including microsomia, micrognathia, retrognathia, orbital hypotelorism and enophthalmos Genetic testing was performed via a custom Whole Exome Slice at GeneDx laboratories and included the MYH3 and TNNI2 genes. Results revealed a heterozygous pathogenic change in MYH3 (c.2015 G>A;p. R6724) consistent with the diagnosis of Freeman-Sheldon syndrome. Conclusion: The presentation of “midline mandibular cleft” on fetal ultrasound was the most specific prenatal finding. This is a very rare fetal finding. Thus, it should prompt further evaluation to assess for true clefting versus ridging or creasing. Additionally, targeted assessment for other findings or clinical clues for Freeman-Sheldon syndrome, such as contractures, “windmill vane” hand, and mouth size, could aid in the differential diagnosis considerations and the diagnostic process. Admittedly, these are position and quality dependent, and are challenging to assess even in ideal situations. The phenotype of the father was immediately recognizable. However, due to COVID-19 pandemic restrictions, prior to the infant’s birth, only telehealth visits were conducted and the father’s participation was by telephone. This limited the ability to narrow the differential diagnosis without visualization of his distinct phenotypic features. Finally, missed opportunities to diagnose the father prior to this pregnancy occurred. Many clinics send “no show” letters to referring providers and patients, as we do. Emphasizing the importance of diagnosis prior to pregnancy for individuals concerned about having a genetic disorder should be considered as part of the information shared in these letters.

DIAGNOSIS OF G6PD DEFICIENCY IN A PATIENT WITH SEVERE RHABDOMYOLYSIS AND SARS-COV-2 INFECTION

Clinicians should have a low threshold for screening for G6PD deficiency in patients with COVID-19 in order to provide effective treatment and avoid complications. B Discussion: b To our knowledge, this is the first report of severe rhabdomyolysis and renal failure in the setting of G6PD deficiency and COVID-19 disease. B Introduction: b Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common enzyme defects worldwide. [Extracted from the article] Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Management of children with glucose-6-phosphate dehydrogenase deficiency presenting with acute haemolytic crisis during the SARs-COV-2 pandemic.

BACKGROUND AND OBJECTIVES: Shortage of blood during the severe acute respiratory syndrome-COV-2 (SARs-COV-2) pandemic impacted transfusion practice. The primary aim of the study is to assess management of acute haemolytic crisis (AHC) in glucose-6-phosphate dehydrogenase(G6PD)- deficient children during SARs-COV-2 pandemic, and then to assess blood donation situation and the role of telemedicine in management. METHODS: Assessment of G6PD-deficient children attending the Emergency Department (ER) with AHC from 1 March 2020 for 5 months in comparison to same period in the previous 2 years, in three paediatric haematology centres. AHC cases presenting with infection were tested for SARs-COV-2 using RT-PCR. Children with Hb (50-65 g/L) and who were not transfused, were followed up using telemedicine with Hb re-checked in 24 h. RESULTS: A 45% drop in ER visits due to G6PD deficiency-related AHC during SARs-COV-2 pandemic in comparison to the previous 2 years was observed. 10% of patients presented with fever and all tested negative for COVID-19 by RT-PCR. 33% of patients had Hb < 50 g/L and were all transfused. 50% had Hb between 50 and 65 g/L, half of them (n = 49) did not receive transfusion and only two patients (4%) required transfusion upon follow up. A restrictive transfusion strategy was adopted and one of the reasons was a 39% drop in blood donation in participating centres. CONCLUSION: Fewer G6PD-deficient children with AHC visited the ER during SARs-COV-2 and most tolerated lower Hb levels. Telemedicine was an efficient tool to support their families. A restrictive transfusion strategy was clear in this study.

Human Leukocyte Antigen Complex and Other Immunogenetic and Clinical Factors Influence Susceptibility or Protection to SARS-CoV-2 Infection and Severity of the Disease Course. The Sardinian Experience.

Aim: SARS-CoV-2 infection is a world-wide public health problem. Several aspects of its pathogenesis and the related clinical consequences still need elucidation. In Italy, Sardinia has had very low numbers of infections. Taking advantage of the low genetic polymorphism in the Sardinian population, we analyzed clinical, genetic and immunogenetic factors, with particular attention to HLA class I and II molecules, to evaluate their influence on susceptibility to SARS-CoV-2 infection and the clinical outcome. Method and Materials: We recruited 619 healthy Sardinian controls and 182 SARS-CoV-2 patients. Thirty-nine patients required hospital care and 143 were without symptoms, pauci-symptomatic or with mild disease. For all participants, we collected demographic and clinical data and analyzed the HLA allele and haplotype frequencies. Results: Male sex and older age were more frequent in hospitalized patients, none of whom had been vaccinated during the previous seasonal flu vaccination campaignes. Compared to the group of asymptomatic or pauci-symptomatic patients, hospitalized patients also had a higher frequency of autoimmune diseases and glucose-6-phosphate-dehydrogenase (G6PDH) deficiency. None of these patients carried the beta-thalassemia trait, a relatively common finding in the Sardinian population. The extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 [OR 0.1 (95% CI 0-0.6), Pc = 0.015] was absent in all 182 patients, while the HLA-C*04:01 allele and the three-loci haplotype HLA-A*30:02, B*14:02, C*08:02 [OR 3.8 (95% CI 1.8-8.1), Pc = 0.025] were more frequently represented in patients than controls. In a comparison between in-patients and home care patients, the HLA-DRB1*08:01 allele was exclusively present in the hospitalized patients [OR > 2.5 (95% CI 2.7-220.6), Pc = 0.024]. Conclusion: The data emerging from our study suggest that the extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 has a protective effect against SARS-CoV-2 infection in the Sardinian population. Genetic factors that resulted to have a negative influence on the disease course were presence of the HLA-DRB1*08:01 allele and G6PDH deficiency, but not the beta-thalassemic trait. Absence of influenza vaccination could be a predisposing factor for more severe disease.

Glucose-6-Phosphate Dehydrogenase Deficiency-Associated Hemolytic Anemia and Methemoglobinemia in a Patient Treated With Hydroxychloroquine in the Era of COVID-19.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder of red blood cells worldwide. The severity of hemolytic anemia varies among individuals with G6PD deficiency, depending on the genetic variant in the G6PD gene; this makes the diagnosis of the condition more challenging in some cases. In this report, we present a case of severe hemolytic anemia and methemoglobinemia in a patient with G6PD deficiency who had been exposed to hydroxychloroquine prescribed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To the best of our knowledge and based on a literature search, this is one of the first case reports in the literature about hemolytic crisis and methemoglobinemia in a patient with critical illness due to severe coronavirus disease 2019 (COVID-19) who was exposed to hydroxychloroquine. It is critical for physicians and caregivers to recognize the effects of oxidative stressors such as hydroxychloroquine, particularly in this era of the COVID-19 pandemic and in regions with a high prevalence of G6PD deficiency, for the appropriate management of this unique subset of patients.

COVID-19 may enhance risk of thrombosis and hemolysis in the G6PD deficient patients.

COVID-19 has become a major public health problem since December, 2019 and no highly effective drug has been found until now. Numbers of infected people and deaths by COVID-19 are increasing every day worldwide, therefore self-isolation and protection are highly recommended to prevent the spread of the virus and especially to protect major risk groups such as the elderly population and people with comorbidities including diabetes, hypertension, cancer, cardiovascular diseases and metabolic syndrome. On the other hand, young people without any secondary disease have died by COVID-19 as well. In this study we compared two male patients infected by COVID-19 at the same age and one of them was diagnosed with G6PD deficiency. Both COVID-19 and G6PD deficiency enhance the risk of hemolysis and thrombosis. Serum biochemistry, hemogram and immunological parameters showed that risk of hemolysis and thrombosis may increase in the G6PD deficient patient infected by COVID-19.

Centrality of G6PD in COVID-19: The Biochemical Rationale and Clinical Implications.

Introduction: COVID-19 is a novel and devastating disease. Its manifestations vary from asymptomatic to lethal. Moreover, mortality rates differ based on underlying health conditions and ethnicity. We investigated the biochemical rationale behind these observations using machine reasoning by the sci.AI system (https://sci.ai/). Facts were extracted and linked from publications available in nlm.nih.gov and Europe PMC to form the dataset which was validated by medical experts. Results: Based on the analysis of experimental and clinical data, we synthesized detailed biochemical pathways of COVID-19 pathogenesis which were used to explain epidemiological and clinical observations. Clinical manifestations and biomarkers are highlighted to monitor the course of COVID-19 and navigate treatment. As depicted in the Graphical Abstract, SARS-CoV-2 triggers a pro-oxidant (PO) response leading to the production of reactive oxygen species (ROS) as a normal innate defense. However, SARS-CoV-2's unique interference with the antioxidant (AO) system, through suppression of nitric oxide (NO) production in the renin- angiotensin-aldosterone system (RAAS), leads to an excessive inflammatory PO response. The excessive PO response becomes critical in cohorts with a compromised AO system such as patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd) where NO and glutathione (GSH) mechanisms are impaired. G6PDd develops in patients with metabolic syndrome. It is mediated by aldosterone (Ald) which also increases specifically in COVID-19. Conclusion: G6PD is essential for an adequate immune response. Both G6PDd and SARS-CoV-2 compromise the AO system through the same pathways rendering G6PDd the Achilles' heel for COVID-19. Thus, the evolutionary antimalarial advantage of the G6PDd cohort can be a disadvantage against SARS-CoV-2.

Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine.

Glucose 6-phosphate dehydrogenase (G6PD) deficiency facilitates human coronavirus infection due to glutathione depletion. G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by N-acetylcysteine (NAC) administration. We describe a severe case of COVID-19 infection in a G6PD-deficient patient treated with hydroxychloroquine who benefited from intravenous (IV) NAC beyond reversal of hemolysis. NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein (CRP), and ferritin and allowed removal from respirator and veno-venous extracorporeal membrane oxygenator and full recovery of the G6PD-deficient patient. NAC was also administered to 9 additional respirator-dependent COVID-19-infected patients without G6PD deficiency. NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients. NAC mechanism of action may involve the blockade of viral infection and the ensuing cytokine storm that warrant follow-up confirmatory studies in the setting of controlled clinical trials.