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Home , Anemia, Blood test, Ferritin, Hypoalbuminemia, Pallor, Serum iron

A Case of a 15-Month-Old With Periorbital and Severe Audrey D. Kamzan, MD, Charles A. Newcomer, MD, Laura J. Wozniak, MD, MSHS, Noah C. Federman, MD, Lydia S. Kim, MD, MPH

This is the case of a previously healthy 15-month-old girl who initially abstract presented to her primary pediatrician with a 2-week history of intermittent periorbital edema. The edema had improved by the time of the visit, and a specimen was unable to be obtained in the clinic. A routine fingerstick demonstrated anemia to 8.8 mg/dL, so the patient was started on ferrous sulfate. She then returned to the emergency department 1 month later with severe periorbital edema and but no other significant symptoms. On , she was tachycardic with striking periorbital edema and an otherwise normal physical examination. She was noted to have a severe ( of 3.9 mg/dL and mean corpuscular Mattel Children’s Hospital and University of California, Los Angeles, Los Angeles, California volume of 53.1 fL) and (albumin of 1.9 g/dL and total of 3.3 g/dL). The remainder of her and function test Drs Kamzan, Newcomer, and Kim conceptualized this diagnostic dilemma and drafted the initial results were within normal limits. A urinalysis was sent, which was negative manuscript; Drs Wozniak and Federman contributed for protein. Our panel of experts reviews her case to determine a unifying to drafting the initial manuscript; and all authors diagnosis for both her severe anemia and her hypoalbuminemia. reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work. Dr Kim’s current affiliation is Northern Navajo CASE HISTORY WITH At this visit, it was also noted that Medical Center, Indian Health Service, Shiprock, NM. INPUT a screening hemoglobin had not yet DOI: https://doi.org/10.1542/peds.2019-0391 fi Accepted for publication May 22, 2019 Dr Audrey Kamzan (Pediatric been done; a ngerstick hemoglobin Hospitalist , Moderator) was performed and was 8.8 mg/dL. Address correspondence to Audrey D. Kamzan, MD, Department of , Mattel Children’s Hospital, A 15-month-old girl presented to her Dr Lydia Kim, what were your initial 10833 Le Conte Ave, A2-383 MDCC, Los Angeles, CA primary pediatrician’soffice with a 2- concerns as an outpatient pediatrician? 90095. E-mail: [email protected] week history of intermittent unilateral What is on the differential for this PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, periorbital edema. She had not had any patient with periorbital edema and 1098-4275). recent illness, fever, or changes in urine anemia? Copyright © 2020 by the American Academy of Pediatrics output. Her physical examination in the Dr Lydia Kim (General Pediatrics) clinic was normal with no evidence of FINANCIAL DISCLOSURE: Dr Federman has served edema at the time. Her past medical The mother describes intermittent as a scientific advisory board member for Loxo history and birth history were swelling around 1 eye. With no other and Bayer; the other authors have symptoms, and given the intermittent indicated they have no financial relationships unremarkable; she was born term relevant to this article to disclose. without any complications. Both of the nature of the swelling, I might explore ’ any atopic history the child might have. FUNDING: Dr Federman is supported by the National patient s parents were born in Croatia, Institutes of Health National Center for Advancing She also fits into the classic age range but the patient was born in the United Translational Sciences (grant UL1TR001881). for , so I would States, and there was no history of POTENTIAL CONFLICT OF INTEREST: The authors have want to check a urinalysis for protein. consanguinity. Two months ago, she indicated they have no potential conflicts of interest traveled with her parents to Croatia. The patient also had anemia on her to disclose. There was no significant family history. screening hemoglobin test. On , she had no deficiency anemia (IDA) is the most To cite: Kamzan AD, Newcomer CA, Wozniak LJ, history of fever, weight change, recent common cause of anemia in her age et al. A Case of a 15-Month-Old With Periorbital illness, , bloody or melanotic group and is most frequently Edema and Severe Anemia. Pediatrics. 2020;145(3): e20190391 stools, or change in activity level. attributable to poor nutritional intake,

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 145, number 3, March 2020:e20190391 DIAGNOSTIC DILEMMAS so I would be sure to obtain was 40 breaths per minute with an diagnosis at this point was broad, but a detailed dietary history.1 With an saturation of 96% on room my first concern was to stabilize this otherwise normal history and air. Her weight was 13.3 kg (.99th patient with severe anemia. She is physical examination, I would likely percentile), and her height was hemodynamically stable but certainly treat her empirically with dietary 83.8 cm (95th–98th percentile). On symptomatic from her anemia given changes and oral iron then examination, the patient was well her . My goal was to begin recheck her hemoglobin level. A rise developed and fussy but consolable. slowly correcting her anemia to avoid in hemoglobin of 1 g/dL after She was markedly pale with striking transfusion-associated circulatory 1 month of adequate iron periorbital edema. She appeared overload (TACO). TACO is an supplementation is considered well hydrated with moist mucous incompletely understood diagnostic for IDA.2 I would also send membranes. Her were clear to of transfusions for a level test. Given the auscultation bilaterally with normal that can result in tachycardia, concurrent periorbital edema, I . Her cardiac tachypnea, and and is would have a low threshold for examination demonstrated associated with significant morbidity a broader workup. Renal can tachycardia but no murmur or gallop. and mortality. One proposed also cause anemia, again leading me Her abdominal examination was mechanism is an increase in central to pursue urine testing. normal; her abdomen was soft and venous pressure, which to nontender, and no failure and .3 Dr Kamzan was noted. She Children ,3 years of age are at The patient’s parents mentioned that was noted to have 21 pretibial and increased risk, especially in the they have had a difficult time weaning pedal pitting edema bilaterally. setting of fluid overload, hypoalbuminemia, or cardiac or renal her off the bottle, and she was Initial bloodwork and urine were ’ impairment.4 Although slower drinking large quantities of cow s obtained by the ED . A transfusions and have milk. A bag was placed for urine was significant become routine practice for severe collection, but the patient did not void for a hemoglobin of 3.9 mg/dL and anemia in many centers, the evidence spontaneously in the clinic, so urine of 15.4 with a mean behind these interventions is weak, studies could not be performed. Given corpuscular volume of 53.1 fL. Her especially in pediatrics.5 However, in that the edema had already resolved, white blood count was 15.7 3 light of this patient’s risk factors a catheterized specimen was not felt 103/mL, and her count was (,3 years of age and low albumin), to be necessary. A lead level was 611 000/mL. Her laboratories were , m we felt it prudent to give 2 low- obtained and was 3 g/dL. The also notable for an albumin of volume (5 mL/kg) transfusions back patient was prescribed ferrous sulfate 1.9 g/dL and a total protein of 3.3 g/dL. to back over a total of 8 hours. for treatment of her anemia, and she The remainder of her electrolytes and was scheduled for a follow-up liver function test results were within Given her hypoalbuminemia, appointment in 1 month for normal limits. A urinalysis was sent, a chest radiograph was done before a hemoglobin recheck. The patient which demonstrated a pH of 6.5, transfusion to rule out baseline was instructed to return sooner if the aspecific gravity of 1.011, 3 red blood pulmonary edema and the need for periorbital edema recurred. Three cells, and 2 white blood cells and was diuretics. The patient’s chest weeks later, the patient again otherwise negative, including for radiograph demonstrated a normal developed periorbital edema and protein. cardiac silhouette and normal presented to our emergency fields with no evidence of pulmonary department (ED) for evaluation. Given her severe anemia and edema or . The hypoalbuminemia, a pediatric patient was admitted to our pediatric In the ED, the parents noted that the hospitalist consult was obtained. Dr ward for further workup and periorbital edema was now bilateral Newcomer, as the pediatric management. and, over the last 7 days, had consultant in the ED, what were your progressively worsened. Her urine primary concerns at this point? What Dr Kamzan output was normal, and there was no additional workup did you change in her eating or drinking recommend? What did you think was causing her habits. The results of her review of microcytic anemia? What additional systems remained negative for other Dr Andy Newcomer (Pediatric workup did you recommend? symptoms. Hospitalist Medicine) On ED assessment, the patient was This patient has a chronic, severe Dr Newcomer tachycardic with a heart rate of 187 microcytic anemia as well as The most common causes of beats per minute. Her respiratory rate hypoalbuminemia. My differential microcytic anemia are IDA and a or b

Downloaded from www.aappublications.org/news by guest on September 24, 2021 2 CRUMMEY et al . Less common causes TABLE 1 Laboratory Data include other , Test Laboratory Value , , Albumin, g/dL 3.7–5.1 1.9 and chronic inflammation. The Total protein, g/dL 6.2–8.6 3.3 American Academy of Pediatrics Complete blood count guidelines for the workup of severe White count, K/mL6–17.5 15.7 m – IDA recommend, at a minimum, , K/ L 143 398 611 Hemoglobin, mg/dL 10.5–13.5 3.9 adding and C-reactive Hematocrit, % 33–39 15.4 protein (CRP) to the hemoglobin , fL 70–86 53.1 measurement.6 Serum ferritin is Red cell distribution width, fL 36.9–48.3 56.2 a sensitive marker for iron stores in Ferritin, ng/mL 8–180 a a healthy individual but may also be Iron studies , mg/dL 23–182 ,8 elevated in the setting of anemia of Iron-binding capacity, mg/dL 240–520 b chronic disease. A normal CRP is Saturation, % — b needed to help rule out those CRP, mg/dL ,0.8 ,0.3 confounders and has the added Lead, mg/dL 0–9 ,3.0 – benefit of helping to diagnose anemia count, % 0.99 1.82 0.14 6 Stool studies of chronic disease. Low serum iron A1AT, mg/dL ,55 695 level, reticulocyte count, and elevated Calprotectin, mg/g #50 223 total iron-binding capacity, as well as FOBT Negative Negative an elevated distribution Urinalysis – width, would also support the pH 5.0 8.0 6.5 Specific gravity 1.005–1.030 1.011 diagnosis of IDA. If iron studies were Red blood cells, cells per hpf 0–20 unrevealing, I would consider White blood cells, cells per hpf 0–40 a workup for thalassemia. This Protein Negative Negative patient’s background should raise Hpf, high-power field; —, not applicable. concerns for thalassemia because the a Test not performed because of insufficient quantity of blood. b incidence of b thalassemia in Croatia, Unable to calculate because of low serum iron. where both parents were born, is 7,8 estimated to be 0.8% to 1%. This elicited on history. The parents also the help of a pediatric hematologist. I patient already had 1 normal lead had not been able to get her to take agree with the workup, management, level, which was confirmed on review the ferrous sulfate as prescribed. At and differential thus far as well as the of outpatient records, so there is no this time, iron deficiency due to slow rate of red blood cell transfusion need to send this test again. dietary causes remained highest on and concerns for TACO in this patient. On the basis of the above differential, our differential. The I was asked for consultation in this a more extensive laboratory workup provided her a large dose of iron case because of the severity of anemia was ordered (Table 1). intravenously, and she was started on and hypoalbuminemia potentially oral iron as well. The parents were related to dietary cow’s milk intake. Dr Kamzan also counseled regarding augmenting Although the anemia in this case is ’ What did you learn from this more the patient s dietary iron intake and severe, it is not uncommon in ’ extensive workup? limiting cow s milk intake. toddlers with excessive milk intake and poor dietary iron consumption. Dr Kamzan Dr Newcomer Excessive ingestion of cow’s milk in Dr Federman, does this patient’s children results in IDA due to both The patient’s reticulocyte count was severe anemia seem consistent with poor iron absorption from low low at 0.14%. A serum iron level was excessive milk intake? Are there any bioavailability and, in some cases, also low (,8 mg/dL). A fecal occult other diagnoses that should be occult blood loss from intestinal (FOBT) was sent to rule considered? irritation.9 out gastrointestinal as the source of low iron; multiple FOBTs Dr Noah Federman (Pediatric It is always important to consider were sent, and all had a negative Hematologist-Oncologist) other causes of severe anemia. One result for occult blood. In general, the evaluation and should consider red blood cell The concerns regarding the patient’s management of a child with destruction (eg, ). high cow’s milk intake, sometimes in suspected or confirmed A reticulocyte count and a direct excess of 32 oz per day, were again uncomplicated IDA does not require antiglobulin test are fairly good

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 145, number 3, March 2020 3 screening tests for red cell production others, that could be indicative of an the cause of the patient’s and immune-mediated causes of red underlying or red hypoalbuminemia. Dr Wozniak, does cell destruction, respectively. In this blood cell membranopathy and this case seem consistent with PLE? case, the reticulocyte count was low, resultant . None of these What are the most common causes of and the direct antiglobulin test result were present on my review. PLE in children? was negative, which is consistent with absent or low red blood cell Dr Kamzan Dr Laura Wozniak (Pediatric ) production, not an immune-mediated Dr Newcomer, what about her process. Finally, I always consider hypoalbuminemia? How can you PLE is characterized by abnormal a diagnosis of an underlying explain that? protein loss from the gastrointestinal malignancy in these cases; a careful tract, resulting in history, physical examination, and Dr Newcomer and edema. It is caused by protein leakage across the gut or diminished review of the peripheral blood smear It is useful to think of the causes of . uptake by intestinal lymphatics.11 are critical. The presence of 1 cell hypoalbuminemia as due to either as well as , line abnormality and/or decreased albumin production (poor pleural effusions, and pericardial hepatosplenomegaly should raise or liver dysfunction effusions can be seen. The clinical concern for a malignant etiology. resulting in decreased synthesis) or manifestations vary depending on the an increase in losses (typically Dr Kamzan underlying cause, but most patients through urine or stool). For a child present with diarrhea. This patient Dr Federman, you reviewed the with edema and hypoalbuminemia, did not have diarrhea, but because we peripheral smear. What were your urinary causes of protein loss, such as have already ruled out most other thoughts at this time? nephrotic syndrome, would be at the common causes of hypoalbuminemia, top of my differential; I was surprised the diagnosis of PLE should be Dr Federman by her normal urinalysis result. considered. As a hematologist, I find that review Another possible cause of IDA and of the peripheral smear is critical to hypoalbuminemia is , Dr Kamzan understanding the underlying a severe form of protein energy What are the most common causes of diagnosis and potentially ruling out with edema. It is PLE in children? other diagnoses. It is important to typically seen in low- and middle- remember to perform a peripheral income countries, but there have Dr Wozniak smear before red cell transfusion in been cases reported in the United 10 There are a number of primary and order to avoid confounding the States. This patient was at the 90th secondary causes of PLE (Table 2), interpretation. The smear in this case percentile for both weight and height each of which presents differently. was classic for severe IDA, showing parameters, and a review of the Some examples include inflammatory marked hypochromic, microcytic red patient’s outpatient records bowel disease (IBD), celiac disease, cells of varying sizes, indicating the demonstrated that she had always and gastrointestinal . chronicity of the IDA. There were been .50th percentile for weight and However, many of these are less likely increased platelets of normal size and height, making malnutrition unlikely. given the lack of diarrhea. morphology; thrombocytosis in the With regard to her liver function, her presentation of IDA is common. The and alkaline Dr Kamzan etiology of the thrombocytosis in IDA phosphatase were within normal Is there further workup for the is not entirely understood but may be limits, and her studies patient’s hypoalbuminemia that you due to thrombopoietin stimulation were also normal, confirming would recommend? and/or acting as an acute phase adequate synthetic function. Finally, reactant. The white blood cells were we began to consider stool losses of Dr Wozniak also normal in morphology, and more protein, protein-losing enteropathy At this point, I would recommend importantly, there were no leukemic (PLE), as a possible cause of her further testing for PLE. The diagnosis blast cells appreciated. hypoalbuminemia. of PLE can be established by In review of the peripheral smear, it is measuring fecal a-1 antitrypsin also important to assess for evidence Dr Kamzan (A1AT), a serum protein that is not of other red blood cell disorders, At this time, excessive milk ingestion ingested in the diet. An elevated fecal including the presence of seems to be the most likely cause of A1AT level suggests increased enteral spherocytes, target cells, anisocytes, the patient’s severe IDA. However, protein loss. In most cases, the teardrop cells, elliptocytes, and many we have been unable to elucidate etiology of PLE can be established

Downloaded from www.aappublications.org/news by guest on September 24, 2021 4 CRUMMEY et al TABLE 2 Causes of PLE stool cells present, and an FOBT Mucosal With Inflammation Gastrointestinal tumors had a negative result. The fecal and/or Ulcerations calprotectin was 223 mg/g; sources Graft-versus-host disease differ on the expected normal values : for this age group, so this may be Bacterial: Clostridium difficile, Salmonella, Shigella, Campylobacter, , Clostridium considered either mildly elevated or 13 perfringens normal for age. Celiac titer results Parasitic: Strongyloides stercoralis, Giardia lamblia were negative, and an abdominal Viral: rotavirus, , cytomegalovirus ultrasound with Doppler was within IBD: normal limits. A review of the Crohn disease literature was performed, during Necrotizing enterocolitis which we discovered several case Nonsteroidal anti-inflammatory enteropathy reports identifying an association Mucosal injury without Celiac disease between severe IDA and PLE.14–16 fl in ammation and/or ulcerations The causal link between the 2 Eosinophilic gastroenteritis fi Food-induced enteropathy ndings is unclear, but in published Hypertrophic gastropathy reports, iron therapy and correction Small intestinal bacterial overgrowth of the IDA led to complete resolution Vasculitic disorders: of the PLE.17,18 Given the expectation Systemic erythematosus that the PLE would likely resolve with Henoch-Schonlein purpura Lymphatic abnormalities Primary intestinal lymphangiectasia12 iron therapy, as well as the low Secondary intestinal lymphangiectasia suspicion for other inflammatory Obstructive: Crohn disease, , based on the clinical Elevated lymph pressure: congestive , constrictive presentation and workup, immediate pericarditis, Fontan procedure for single ventricle, portal was not indicated. Syndromal: Hennekam, Klippel-Trenaunay, Noonan, Turner However, close follow-up of this patient is important; if the PLE did not resolve with iron therapy, from a careful history, physical hypertension seems unlikely given endoscopy would be the next step. examination, and laboratory workup; that she has no ascites, , Dr Kamzan endoscopy is rarely necessary to or . However, diagnose the underlying cause. because venous outflow obstruction Dr Newcomer, what were the next (eg, hepatic or portal steps you took in managing this While we wait for the stool A1AT thrombosis) can, on rare occasions, patient? results, I might also consider lead to PLE, I would recommend an Dr Newcomer a preliminary workup for causes of abdominal ultrasound with Doppler. PLE. In our patient, IBD seems The patient continued to have unlikely given that she had no It is important to note that although significant periorbital edema, so she diarrhea and no stool inflammatory milk-protein can lead to was given 2 mL/kg of 25% albumin cells. However, a stool calprotectin, as anemia and potentially PLE as well, I followed by 0.5 mg/kg of . well as an erythrocyte sedimentation had a low suspicion in this case. This This intervention dramatically rate and CRP, would help screen for patient was older (patients typically improved her edema. The patient was fi underlying IBD. Elevated fecal present within the rst year), and the discharged with close follow-up with calprotectin, a granulocyte protein stool was -negative. Both of her primary pediatrician and a plan that plays a role in neutrophil these make milk-protein allergy to repeat a complete blood count and defense, can also be seen in PLE but is unlikely. albumin within 1 week. fi 12 not speci c to the diagnosis. In Dr Kamzan addition, I would recommend celiac Dr Kamzan titers to rule out celiac disease: What were the results of the workup What happened to the patient after antitissue transglutaminase, for PLE? discharge? antiendomysial , and a total immunoglobulin A level. A cardiac Dr Wozniak Dr Kim etiology seems unlikely given that the The patient’s stool A1AT level was After discharge, the patient’s parents patient had a normal heart size on elevated to 695 mg/dL (reference limited cow’s milk in the child’s diet chest radiograph. Likewise, portal range: ,55 mg/dL). There were no (but she continues to consume dairy

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 145, number 3, March 2020 5 products in moderation). They gave literature, but the mechanism is continue to consume dairy products the patient the ferrous sulfate as poorly understood.14–18 Some cases in moderation without recurrence of prescribed, and her albumin and may be explained by milk-protein her PLE or IDA, so we do not feel that hemoglobin continued to uptrend allergy. However, there have been milk-protein allergy played a role in (Fig 1). A repeat A1AT level was reported cases in which there was no her disease process. obtained 2 weeks after discharge, clinical or laboratory evidence of IDA is common in the United States which at that time was undetectable, milk-protein allergy and intestinal and remains the world’s most and the patient’s edema never biopsy results were normal, showing common single-nutrient deficiency returned. Given the improvement in no change in villus structure or among children.19 Therefore, we edema with only treatment of her quantity of intraepithelial suspect there may be an under- iron deficiency, the patient was lymphocytes.15 In published reports recognized burden of PLE in these presumed to have PLE related to of these cases, iron therapy corrected patients. In toddlers, nutritional underlying IDA. both the IDA and the concerns are the most common hypoalbuminemia without switching causes of IDA. Specifically, excessive to a dairy-free diet.17,18 Further cow’s milk intake is known to be an DISCUSSION research is needed to elucidate the important cause due to the This is a case of a common disease causative mechanism of PLE in these content blocking the absorption of process (IDA) presenting with an cases. As described in the literature, iron. It is not uncommon for the unusual sequela (PLE). The patient’s simply by treating this patient’s resulting anemia to be profound, as elevated stool A1AT levels ultimately underlying IDA with iron we saw in this case. There were confirmed the diagnosis of PLE supplementation and limiting cow’s significant safety issues involved with despite the lack of diarrhea or any milk intake, we were able to achieve treating this patient’s anemia; our other suggestive symptoms. An complete resolution of her PLE and team was concerned that the threat association between severe IDA and resulting hypoalbuminemia. of TACO may have been further PLE has been described in the Importantly, the patient was able to heightened by the decreased due to low protein, so we pursued a plan of slow transfusion. For the general pediatrician consulted about a toddler with periorbital edema, nephrotic syndrome should be high on the differential; we were surprised to find her urine to be negative for protein. Our multidisciplinary team was essential in making the diagnosis by employing a systematic approach to the hypoalbuminemia workup. We conceptualized the causes of hypoalbuminemia into 2 groups: decreased production of protein (such as malnutrition and ) and increased losses (in the urine or stool). By ruling out most other causes of hypoalbuminemia, we were left with PLE as the presumptive diagnosis while awaiting the A1AT results. We felt there was likely to be a common cause between the IDA and PLE in this otherwise healthy child. A review of the literature led to the discovery of the many case reports describing the association between FIGURE 1 PLE and IDA. General pediatricians, Case laboratory values over time. who are on the front lines of

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Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2020/02/18/peds.2 019-0391 References This article cites 15 articles, 3 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2020/02/18/peds.2 019-0391#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Community Pediatrics http://www.aappublications.org/cgi/collection/community_pediatrics _sub Community Health Services http://www.aappublications.org/cgi/collection/community_health_se rvices_sub Gastroenterology http://www.aappublications.org/cgi/collection/gastroenterology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 24, 2021 A Case of a 15-Month-Old With Periorbital Edema and Severe Anemia Audrey D. Kamzan, Charles A. Newcomer, Laura J. Wozniak, Noah C. Federman and Lydia S. Kim Pediatrics originally published online February 20, 2020;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2020/02/18/peds.2019-0391

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2020 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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