Weakness, Anemia, and Neutropenia in a 9-Year-Old Girl With Influenza Adam Cohen, MD,a,b Funmilola S. Owolabi, MD,a,b Cicely P. Dowdell-Smith, MD,a,b Jason Laufman, MD,c Ionela Iacobas, MD,a,b Lanessa Bass, MD, MEd,a,b Dana Foradori, MD, MEda,b

A previously healthy 9-year-old immigrant girl from Mexico was evaluated in abstract the emergency department (ED) with one week of fatigue, fevers, rhinorrhea, and cough. She initially presented to her primary pediatrician, where a complete blood count revealed neutropenia, prompting referral to the ED. In the ED, she was found to be influenza A–positive. Because of dehydration, she received intravenous fluids and was admitted to the pediatric hospital medicine service. After 2 days, influenza symptoms improved, and oral intake increased. However, she was noted to have decreased bilateral lower- aTexas Children’s Hospital, Houston, Texas; bBaylor College of fl Medicine, Houston, Texas; and cAkron Children’s Hospital, extremity strength, absent Achilles re exes, decreased lower-extremity Akron, Ohio sensation and proprioception, a positive result on the Romberg sign, and fi Dr Cohen initiated this collaborative project, abnormal heel-to-shin testing results. These ndings prompted an urgent reviewed the literature, recruited and interviewed neurology consultation. After extensive imaging, laboratory evaluation, and all subspecialists, and drafted and edited the further consultations, a diagnosis was established. manuscript; Dr Foradori initiated this collaborative, supervised the recruitment of subspecialists, and critically revised the manuscript; Drs Dowdell-Smith, Laufman, and Iacobas contributed to the writing and revision of the manuscript; Drs Bass and Owolabi CASE HISTORY WITH SUBSPECIALTY In the ED, she was found to be initiated this collaborative, supervised the INPUT influenza A–positive and had an recruitment of the subspecialists, and contributed to absolute neutrophil count (ANC) of 900 the writing and revision of the manuscript; and all Dr Cohen, Pediatric Hospital Medicine ’ cells per µL, with a normal hemoglobin authors were involved in the patients care, approved Fellow, Moderator the final manuscript as submitted, and agree to be level and a normal platelet count. She accountable for all aspects of the work. A previously healthy 9-year-old girl was initially febrile to 39.5°C, with DOI: https://doi.org/10.1542/peds.2019-2574 presented to the emergency a pulse of 134 beats per minute and department (ED) with 12 days of blood pressure of 136/61 mm Hg. After Accepted for publication Nov 7, 2019 symptoms that included fatigue, a 20-mL/kg normal saline bolus and Address correspondence to Adam Cohen, MD, congestion, cough, and fever. She Section of Pediatric Hospital Medicine, Feigin Center, antipyretic administration, her energy ’ presented to her primary pediatrician Texas Childrens Hospital, 18th Floor, 1102 Bates Ave, and vital signs improved. However, she Houston, TX 77030. E-mail: [email protected] 9 days before and was started on still felt weak when walking. She was PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, amoxicillin for acute otitis media. started on oseltamivir and admitted to 1098-4275). Despite adherence to the antibiotics, the pediatric hospital medicine service Copyright © 2020 by the American Academy of she developed progressive lower- for further supportive care. Pediatrics extremity weakness and pain, Dr Owolabi, what is your typical FINANCIAL DISCLOSURE: The authors have indicated worsening fatigue, and emesis. On the admission criteria for influenza, and they have no financial relationships relevant to this day of presentation, she developed how do you manage a child with article to disclose. a fever to 39.5°C. She also refused to influenza admitted to the hospital? FUNDING: No external funding. walk because of weakness. She was Does this patient’s neutropenia change POTENTIAL CONFLICT OF INTEREST: The authors have reevaluated by her pediatrician and your approach to their condition? indicated they have no potential conflicts of interest was found to be neutropenic, to disclose. prompting referral to the ED. On Dr Funmilola Owolabi, Pediatric further history, the patient had been Hospital Medicine To cite: Cohen A, Owolabi FS, Dowdell-Smith CP, exposed to an aunt with an influenza- Hospitalization may be necessary if et al. Weakness, Anemia, and Neutropenia in a fl like illness just before onset of a child develops severe symptoms or 9-Year-Old Girl With In uenza. Pediatrics. 2019; 145(5):e20192574 symptoms. complications of influenza. Nausea and

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 145, number 5, May 2019:e20192574 DIAGNOSTIC DILEMMAS vomiting, 2 commonly presenting Dr Cohen limited despite improvement in fl symptoms in children, can lead to The patient arrived at the inpatient her other symptoms of in uenza. fi dehydration, prompting the need for unit of the hospital and was noted Additional examination ndings intravenous hydration. Upper to be well-appearing. Vital signs were concerning for an underlying respiratory symptoms can progress included a temperature of 37.7°C, neurologic process, yet the primary fi to lower airway disease, leading to a pulse of 108 beats per minute, and cause of dysfunction was dif cult to hypoxemia and respiratory distress a blood pressure of 104/59 mm Hg. pinpoint. There were concerns for necessitating supplemental oxygen or The patient’s weight was at the fifth cerebellar, proprioceptive, and even a higher level of respiratory support. percentile for age, her height was at possible lower motor neuron or Concern for a bacterial superinfection the 43rd percentile for age, and her peripheral sensory dysfunction on the may prompt initiation of antibiotics. BMI was at the first percentile for age. basis of her examination. Given the Children with underlying chronic She was thin but well hydrated, with reason for her initial hospitalization, illnesses, such as asthma, congenital normal cardiac, pulmonary, and postinfectious etiologies, such as heart disease, or immunosuppression, abdominal examination results. At acute cerebellar ataxia and Guillain- are at higher risk of complications that point, gait was not assessed. Barré syndrome, were highest on the and therefore can require closer differential. 1 Over the next 3 days, her influenza monitoring. Ultimately, the need for At this point, pediatric neurology was symptoms of fever and emesis both additional supportive care outside of consulted. oral rehydration, antipyretics, and improved. She was noted to have bed rest is indicative of a more severe adequate lower-extremity muscle Dr Cohen illness and likely a need for strength. Myalgias of the lower Dr Dowdell-Smith, how do you hospitalization. extremities improved, but she was distinguish between the different requiring some assistance to walk. etiologies of abnormal gait? Is this an Although management is primarily Intravenous fluids were weaned, and area in which your examination can supportive, national guidelines pain was controlled on oral help you “localize” the lesion? recommend that children hospitalized medications. Before discharge, her fl with in uenza should be treated with ambulation was more formally Dr Cicely Dowdell-Smith, Pediatric oseltamivir regardless of their evaluated and revealed a broad-based Neurology duration of symptoms.2 In reality, gait with poor balance and inability to Abnormal gait is a general antiviral use in children hospitalized ambulate independently. Bilateral description. Therefore, using specific with influenza varies by practice.3 lower-extremity strength was 4/5, terminology is important when Concerns regarding the side-effect with absent Achilles reflexes requesting consultation. The profile of antiviral agents, the bilaterally but 21 patellar reflexes. differential diagnosis varies widely subjective classification of “severe She also had grossly decreased for a child with an abnormal gait disease,” and overall perceived lower-extremity sensation and depending on whether it is due to benefits may impact provider proprioception, a positive result on a limp, ataxia, or weakness. Weakness prescribing behaviors.4 Our the Romberg sign, and abnormal may cause a staggering and off- patient was started on oseltamivir at heel-to-shin testing results. Lower- balance gait that is not truly ataxic. In the time of admission and completed extremity musculature was mildly this case, the hospitalist was clearly a 5-day course during her tender. describing an ataxic gait, which is hospitalization. Dr Owolabi, what was your thought often described as wide based and The patient’s neutropenia did not process when confronted with these drunken. The differential diagnosis fi change my initial approach. At the new examination ndings? for this type of gait is broad and also time of admission, neutropenia was includes sensory ataxia from moderate (ANC of 900 cells per µL). Dr Owolabi proprioceptive impairments. In the setting of a viral infection, The patient’s inability to walk, On the basis of the patient’s recent neutropenia can be caused by weakness, and muscle tenderness influenza infection, the first thought transient bone marrow were initially thought to be secondary in this patient was acute cerebellar suppression5,6 and therefore should to viral myositis. In the setting of ataxia. This diagnosis accounts for up resolve. Persistent neutropenia after influenza, myositis is commonly to 50% of all cases of cerebellar illness resolution or the development reported in the calves and may ataxia.7 However, acute cerebellar of concomitant anemia or impact weight bearing.2 However, her ataxia is a diagnosis of exclusion. An thrombocytopenia, however, would creatinine kinase level was normal, additional postinfectious etiology of broaden my differential. and ambulation remained severely ataxia is Guillain-Barré syndrome, an

Downloaded from www.aappublications.org/news by guest on September 26, 2021 2 COHEN et al immune-mediated polyneuropathy made it difficult to assess beyond this symptoms before her initial most commonly presenting as (Fig 1). After discussion with the presentation with influenza. However, ascending weakness. Intracranial neuroradiology team, this finding is signs and symptoms became more etiologies of acute ataxia include consistent with subacute combined apparent through the course of her brainstem and cerebellar tumors, degeneration of the spinal cord, hospitalization. Her MRI findings are intracranial infection, ischemic or a condition most frequently seen in highly characteristic of B12 deficiency. hemorrhagic stroke, and intracranial vitamin B12, or cobalamin, deficiency. B12 deficiency may be due to demyelinating processes. Although these findings are highly decreased absorption of B12, inability Additionally, toxin exposure, inborn suggestive of B12 deficiency, the to properly use B12, and, less likely in errors of metabolism (IEMs), and physician should consider a broader this case, exposure to a toxin, such as trauma also can cause acute onset of array of differential diagnoses such as nitric oxide, that results in 9 ataxia but were felt to be less likely inflammatory conditions (such as inactivation of B12. on the basis of this patient’s multiple sclerosis or acute presentation. disseminated encephalomyelitis ), Dr Cohen infectious myelitis, or atypical Additional findings on the physical malignancy. Suspicion for alternate Additional focused histories were examination may be helpful in trying diagnoses should be based on obtained. It was discovered that the to localize the origin of neurologic fi additional supporting findings on child had dif culty walking after signs and symptoms. It is always ∼ history, examination, laboratory exercise in school 2 weeks before important to recognize abnormal vital fl values, and imaging. the onset of in uenza. In addition, her signs as a potential indicator of diet was primarily restricted to increased intracranial pressure. Dr Dowdell-Smith, how does this simple carbohydrates, with a paucity Abnormal mental status may suggest change your differential diagnosis, of meats, poultry, legumes, and acute disseminated encephalomyelitis and what diagnoses concern you the vegetables. or intracranial infection. Headaches, most in a patient with these findings? vomiting, focal neurologic With her low BMI (first percentile abnormalities, cranial neuropathies, Dr Dowdell-Smith z score 22.5), there was concern for or papilledema are associated with possible malabsorption leading to Subacute combined degeneration was posterior fossa tumors. Findings vitamin deficiency. Gastroenterology an unexpected finding in this patient. specific to the cerebellum include was consulted and recommended This appears on the MRI as speech abnormalities, difficulty with additional screening laboratory tests a degeneration of the dorsal and coordination of voluntary movement for celiac disease as well as stool lateral white matter of the spinal (finger to nose, dysdiadochokinesia), studies to evaluate for inflammation cord. Subacute degeneration of the and tremor. Fevers are typically and malabsorption. spinal cord typically presents with associated with infectious causes ataxia, slowly evolving weakness, and such as meningitis, encephalitis, Screening thyroid testing revealed sensory abnormalities8; the patient labyrinthitis, and intracranial a low thyroid-stimulating hormone reported none of these signs or m abscesses. Guillain-Barré syndrome level of 0.3 IU/mL (normal range – typically presents with symmetric 0.7 4) and a high-normal free ascending weakness, decreased or thyroxine level of 1.8 ng/dL (normal – absent reflexes, and sensory range 0.8 2). Endocrinology was symptoms. The Miller-Fisher variant consulted for further guidance. A may present differently with external diagnosis of pernicious anemia and ophthalmoplegia, ataxia, and autoimmune polyglandular syndrome areflexia. was considered given its association with both malabsorption and Dr Cohen hyperthyroidism. However, further laboratory evaluation revealed We obtained an MRI of the brain and negative results, and her laboratory spine with and without contrast. The FIGURE 1 tests were felt to be more consistent MRI of the brain was normal. Axial T2 MRI image of the spine at the level of with sick euthyroid syndrome. However, the MRI of the spinal cord the dens. The red circle is highlighting the spinal cord with bilateral-symmetric increased revealed symmetric, bilateral T2 Despite the concern for B12-related signal intensity within the dorsal signal intensity of the dorsal columns. This subacute combined degeneration of image was used with permission of the family columns from the level of C2 to at and Texas Children’s Hospital Department of the spinal cord, B12 and folic acid least the level of T2, although artifact Radiology. levels returned normal.

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 145, number 5, May 2019 3 Homocysteine and methylmalonic patient underwent extensive to be the next step in solidifying the acid levels were pending. investigations to rule out the other diagnosis. possible causes. A repeat complete blood count The patient had a restrictive diet that revealed a downtrend of the ANC of As mentioned above, malignant put her at risk for B12 deficiency, but µ 296 cells per L, a downtrend of the processes were also on the insufficient dietary intake of B12 is hemoglobin level of 11 g/dL (with differential, and the peripheral smear rare in children.12 Given the patient’s a mean cell volume of 94 fL; age was analyzed multiple times during age and the acuity of the presenting normal range 76–90), and the admission for confirmation. No symptoms, we were also concerned a downtrend of the platelet count of leukemic blasts or other malignant about a metabolic cause for her 3 141 3 10 /µL. Given the concern for cells were reported. We considered symptomatology. inflammatory lesions in the spinal bone marrow aspiration and biopsy, cord and new pancytopenia, oncology but when the homocysteine level Dr Cohen was consulted with concern for resulted, the procedure was canceled Dr Laufman, most commonly, we possible malignancy. and attention was turned completely worry about metabolic diseases Dr Iacobas, how do you think through toward a metabolic etiology. presenting catastrophically in infancy, the differential diagnosis in a child but this child presented with with pancytopenia, and what special Dr Cohen symptoms concerning for a metabolic considerations are present in this Results of multiple studies returned disease in late childhood. When case? negative, including folate level and should we be concerned about a metabolic disease in older children? Dr Ionela Iacobas, Pediatric viral studies for Epstein-Barr virus, How do you make sense of this Hematologist and Oncologist cytomegalovirus, HIV, and parvovirus B19. The homocysteine level returned patient with disparate laboratory Pancytopenia during or immediately as .100 µmol/L. Dr Owolabi, how did values? after a viral illness is common in you make sense of a normal B12 and pediatrics. Usually it is not folate level but a homocysteine level Dr Jason Laufman, Pediatric a concerning sign, but extensive that was too high to be measured? Genetics Fellow education is offered to the family, What was your next step? Many rightly suspect an IEM in the including neutropenic precautions infant with lethargy, poor feeding, and close monitoring by the Dr Owolabi acidosis, or hyperammonemia. hematologist or primary physician However, IEMs may present with On the basis of the clinical picture and until the counts recover. In our case, a wide array of signs and symptoms, imaging, it was presumed that there the thrombocytopenia was minimal and a number of these conditions are 3 3 µ would be evidence of a B deficiency. (141 10 / L; normal values would 12 not included on the newborn screen . 3 3 µ Despite the normal B value, serum be 150 10 / L), the neutropenia 12 (NBS). The NBS identifies many 3 3 assays are a poor indicator of B was severe (ANC reached 300 10 / 12 metabolic conditions with high µ . 3 deficiency because they do not L; normal values would be 1500 morbidity and/or mortality, but other 3 µ correlate with tissue stores.11 10 / L), and the hemoglobin level metabolic diseases may not present Intermediate amino acids, such as was minimally decreased. Still, all of until later in life either because of the homocysteine and methylmalonic these numbers could have been natural history the condition or acid, are more useful because their explained by viral-induced bone because of a milder presentation of metabolism is dependent on the marrow suppression. a classically severe condition. presence of B and folate within the In this case, the moderate 12 Unfortunately, there are no objective tissue. macrocytosis of the red blood cells standards for when to evaluate for an was unusual. In patients with normal Homocysteine levels can be elevated IEM. Generally, a clinician should hematopoiesis, the most common in both folate and B12 deficiency. consider IEMs in patients who have cause of macrocytosis is However, the serum folate level was abnormal and unexpected data on reticulocytosis.10 Macrocytosis of red normal, and folate deficiency is not routine laboratory tests or imaging, blood cells without a high usually associated with neurologic especially combined with unusual or reticulocyte count can be due to changes or this patient’s MRI findings. unexplained findings on history or vitamin B12, folate, vitamin B1,or In contrast, an elevated examination. Moreover, the index of copper deficiency as well as methylmalonic acid level is indicative suspicion should be high in children medications, toxins, hypothyroidism, of B12 deficiency. At this point, born outside of the United States. or myelodysplastic syndromes confirming elevation of the serum Each country’s, or even each region’s, associated with trisomy 21. Our methylmalonic acid level was thought NBS program, including economical

Downloaded from www.aappublications.org/news by guest on September 26, 2021 4 COHEN et al support and technologies used, varies metabolism, is often detected on NBS metabolic testing results, such as widely and is rapidly changing.13 It with elevated C3 levels on tandem plasma amino acids, urine organic can often be difficult or time mass spectrometry, but other acids, and the acylcarnitine profile, consuming to track down an disorders of intracellular cobalamin were normal. After treatment with international NBS or even accurately metabolism may not be evident on intramuscular B12 and betaine, the determine which diseases are NBS.14 Younger patients can present homocysteine level normalized, and screened for. with poor feeding, encephalopathy, she began to have improved lower- developmental delay, seizures, and extremity strength and reflexes but In the case of disorders of poor growth. Older individuals can continued to have an ataxic gait. intracellular metabolism of vitamin present with neuropsychiatric Because of persistent difficulty with B12 (cobalamin), presentation can be symptoms, cytopenias (including ambulation, proprioception, and any time from in utero to adulthood. megaloblastic anemias with normal activities of daily living, she was

Cobalamin undergoes endocytosis B12 and folate levels), thrombosis discharged to a pediatric and multiple modifications, all which (including stroke), and subacute rehabilitation unit. With intensive can be affected by IEMs. It is vital for combined degeneration of the spinal rehabilitation, she was able to the conversion of homocysteine to cord.15 In this case, a disorder of improve her functional status, methionine as well as intracellular cobalamin metabolism walking partially independently and methylmalonyl–coenzyme A (CoA) to was correctly suspected on the basis partially with the help of a walker, succinyl-CoA (Fig 2). Depending on of the radiographic findings of with improved energy and resolution the particular enzyme involved, subacute degeneration of the spinal of all pain. She continued to have patients with disorders of cord with normal B12 levels and impaired proprioception but intracellular cobalamin metabolism elevated homocysteine levels. otherwise was neurologically intact. can have elevated homocysteine levels with low methionine and/or Dr Cohen FINAL THOUGHTS AND DISCUSSION elevated methylmalonic acid levels. The methylmalonic acid level Cobalamin C deficiency, the most returned elevated to 57.1 µmol/L Dr Cohen common error of cobalamin (normal range 0–0.5 µmol/L). Other In the initial evaluation of this patient, her symptoms were attributed to the diagnosis of influenza infection, a common cause of myalgias and generalized weakness in children. However, as her course evolved and her influenza symptoms improved, her lower-extremity examination became progressively more striking. Clues about her underlying diagnosis became more apparent later in her clinical course, including a history of difficulty walking preceding the symptoms of influenza and an examination more consistent with coordination deficits than weakness. This history helped this multidisciplinary team to follow a logical and stepwise approach in the evaluation and diagnosis of the child’s condition. After the complete evaluation by genetics, a cobalamin metabolism disorders panel was sent, and 1 FIGURE 2 heterozygous pathogenic variant and Intracellular cobalamin metabolism begins with endocytosis of cobalamin and transcobalamin. 1 heterozygous, likely pathogenic Transcobalamin is removed within the lysosome. Cobalamin then undergoes multiple reductions before aiding in the conversion of homocysteine to methionine and methylmalonyl-CoA to succinyl- variant in the MMACHC gene were CoA. Errors along this pathway may cause elevation of homocysteine and/or methylmalonic acid. found. The pathogenic variant is

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 145, number 5, May 2019 5 associated with methylmalonic CONCLUSIONS 4. Rothberg MB, Bonner AB, Rajab MH, Kim HS, Stechenberg BW, Rose DN. Effects of aciduria and homocystinuria The case of this young girl stresses (cb1C type), the most common local variation, specialty, and beliefs on the importance of recognizing and antiviral prescribing for influenza. Clin inborn error of cobalamin fi fi pursuing signi cant ndings when Infect Dis. 2006;42(1):95–99 metabolism. they are not consistent with the 5. Segel GB, Halterman JS. Neutropenia in presumed diagnosis. In this case, the pediatric practice. Pediatr Rev. 2008; progressive lower-extremity and gait Dr Laufman 29(1):12–23; quiz 24 abnormalities were inconsistent with 6. Walkovich K, Boxer LA. How to approach IEMs can present in diverse and her improving influenza symptoms, neutropenia in childhood. Pediatr Rev. unexpected ways. As such, the prompting further careful evaluation 2013;34(4):173–184 clinician must maintain a high level of and imaging. Vitamin B12 deficiency suspicion in cases in which the signs should be included within the 7. Salas AA, Nava A. Acute cerebellar ataxia in childhood: initial approach in the and symptoms do not fit a classic differential of a child presenting with emergency department. Emerg Med J. presentation of disease. In this case, abnormalities of gait and lower- 2010;27(12):956–957 an IEM was appropriately suspected extremity proprioception, especially and supported with biochemical in children with abnormal diets, 8. Katsaros VK, Glocker FX, Hemmer B, Schumacher M. MRI of spinal cord and screening laboratory tests, including malabsorption, or cytopenias. brain lesions in subacute combined an acylcarnitine profile and total degeneration. Neuroradiology. 1998; plasma homocysteine, plasma ACKNOWLEDGMENT 40(11):716–719 methylmalonic acid, and urine organic acid levels. We thank Dr Huy Tran, MD 9. Whitehead VM. Acquired and inherited (neuroradiologist at Baylor College of disorders of cobalamin and folate in Definitive diagnosis of an IEM is Medicine and Texas Children’s children. Br J Haematol. 2006;134(2): 125–136 achieved with molecular genetic Hospital), for helping us review and testing. Identification of specific IEMs prepare the MRI images of the 10. d’Onofrio G, Chirillo R, Zini G, Caenaro G, is important for initiating therapies patient. Tommasi M, Micciulli G. Simultaneous to slow progression, prevent measurement of reticulocyte and red blood cell indices in healthy subjects intermittent decompensations, guide and patients with microcytic and ABBREVIATIONS appropriate medical screening, or, in macrocytic anemia. Blood. 1995;85(3): this case, reverse symptoms of the ANC: absolute neutrophil count 818–823 disease. Additionally, identification of CoA: coenzyme A 11. Hunt A, Harrington D, Robinson S. IEMs can facilitate screening of other ED: emergency department Vitamin B12 deficiency. BMJ. 2014;349: family members who may be at risk IEM: inborn error of metabolism g5226 and allow for early treatment before NBS: newborn screen 12. Rasmussen SA, Fernhoff PM, Scanlon KS. manifestation of the disease. Our Vitamin B12 deficiency in children and patient’s asymptomatic brother adolescents. JPediatr. 2001;138(1): underwent screening and was found 10–17 to have elevated homocysteine levels. 13. Cantú-Reyna C, Zepeda LM, Montemayor Molecular confirmation of his REFERENCES R, et al. Incidence of inborn errors of diagnosis is pending, but he has been 1. Committee on Infectious Diseases. metabolism by expanded newborn started on hydroxycobalamin. Recommendations for prevention and screening in a Mexican hospital. control of influenza in children, J Inborn Errors Metab Screen. 2016;4: In the cases of disorders of 2018–2019. Pediatrics. 2018;142(4): 1–8 intracellular cobalamin metabolism, e20182367 14. Sloan JL, Carrillo N, Adams D, Venditti the mainstay of therapy is parenteral 2. American Academy of Pediatrics. CP. Disorders of intracellular cobalamin administration of hydroxycobalamin, Influenza. In: Kimberlin DW, Brady MT, metabolism. In: Adam MP, Ardinger HH, which has been shown to be more Jackson MA, Long SS, eds. Red Book: Pagon RA, et al, eds. GeneReviews. effective than other formulations, 2018-2021 Report of the Committee on Seattle, WA: University of Washington, including oral hydroxycobalamin. Infectious Diseases. 31st ed. Itasca, IL: Seattle; 1993 For disorders with American Academy of Pediatrics; 2018: 15. Huemer M, Diodato D, Schwahn B, et al. – hyperhomocysteinemia, such as 476 490 Guidelines for diagnosis and cobalamin C deficiency, we may 3. Williams JT, Cunningham MA, Wilson KM, management of the cobalamin-related consider the use of betaine to Rao S. Rising oseltamivir use among remethylation disorders cblC, cblD, cblE, convert homocysteine into hospitalized children in a postpandemic cblF, cblG, cblJ and MTHFR deficiency. methionine.15 era. Hosp Pediatr. 2016;6(3):172–178 J Inherit Metab Dis. 2017;40(1):21–48

Downloaded from www.aappublications.org/news by guest on September 26, 2021 6 COHEN et al Weakness, Anemia, and Neutropenia in a 9-Year-Old Girl With Influenza Adam Cohen, Funmilola S. Owolabi, Cicely P. Dowdell-Smith, Jason Laufman, Ionela Iacobas, Lanessa Bass and Dana Foradori Pediatrics originally published online March 6, 2020;

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Downloaded from www.aappublications.org/news by guest on September 26, 2021 Weakness, Anemia, and Neutropenia in a 9-Year-Old Girl With Influenza Adam Cohen, Funmilola S. Owolabi, Cicely P. Dowdell-Smith, Jason Laufman, Ionela Iacobas, Lanessa Bass and Dana Foradori Pediatrics originally published online March 6, 2020;

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