Unusual Presentation of Cow’s Milk Protein Allergy : JPGN Reports

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Case Report: Gastroenterology

Unusual Presentation of Cow’s Milk Protein Allergy

Cresoe, Samantha MD*; Setya, Aniruddh MD; Beasley, Genie MD*; Gonzalo, David Hernandez MD§; Chan, Albert MD*

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JPGN Reports 3(4):p e246, November 2022. | DOI: 10.1097/PG9.0000000000000246
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The most common food allergen in infants and young children is cow’s milk protein, which results from an abnormal immunologic response against bovine milk protein (1). Cow’s milk protein allergy (CMPA) is a non-IgE mediated reaction to proteins found in cow’s milk, which if persistent beyond infancy, is often termed food protein-induced enterocolitis syndrome. This differs from classic IgE-mediated food reactions, which occur within minutes to 2 hours of exposure and can include urticaria, angioedema, cough, wheezing, respiratory distress, severe abdominal pain, and vomiting (1). Symptoms of CMPA can include vomiting, diarrhea, rectal bleeding, and irritability. If symptoms are unrecognized and untreated, protein-losing enteropathy, hypoalbuminemia, and poor growth may ensue. Diagnosis of CMPA is made based on a high index of clinical suspicion (2). Due to the various presentations of CMPA, it can mimic several other disease processes. Here, we describe an unusual presentation of severe CMPA that was obscured by clinical and histological features of abetalipoproteinemia.


A 7-month-old male born at 39 weeks gestation with a history of severe atopic dermatitis presented to the emergency department for evaluation of distress, lethargy, and poor growth. The infant was exclusively breastfed and reportedly had daily episodes of nonbloody, nonbilious emesis and 10–14 nonbloody, mucus-containing stools per day.

On physical examination, he was a cachectic, ill appearing infant with tachypnea and tachycardia. His weight was 4.16 kg. Mucus membranes were dry, and he was hypotonic with alopecia and severe atopic dermatitis.

His growth chart revealed that his weight had fallen from the 40th percentile at 2 months of age to below the 1st percentile (Fig. 1). Initial laboratory studies were significant for a serum sodium of 120 mmol/L with serum osmolality of 254 mOsm/kg along with a normocytic anemia, and thrombocytopenia (Table 1).

Table 1. - Initial complete blood count panel and comprehensive metabolic panel obtained upon presentation to the emergency department as well as subsequent lab evaluation obtained throughout hospitalization.
Serum Patient value Reference range and units
WBC 17.2 6.0–17.5 thou/cu mm
RBC 3.63 3.10–4.50 × 10E6/uL
Hemoglobin 9.4 (L) 9.5–13.5 g/dL
Hematocrit 27.2 (L) 29.0%–41.0%
MCV 75 74.0–108.0 fl
MCH 26 25.0–35.0 pg
MCHC 34.7 31.0–37.0 g/dL
RDW 14.7 (H) 11.0%–14.0%
Platelet count 1156 (H) 150–450 thou/cu mm
MPV 5.9 (L) 6.0–10.0 fl
Sodium 120 (L) 136–145 mmol/L
Potassium 5.1 3.3–5.1 mmol/L
Chloride 98 98–107 mmol/L
CO2 15 (L) 22–30 mmol/L
Urea nitrogen 10 6–21 mg/dL
Creatinine <0.20 0.10–0.36 mg/dL
Glucose 100 (H) 65–99 mg/dL
Calcium 7.8 (L) 8.4–10.2 mg/dL
Total protein 3.8 (L) 6.4–8.3 g/dL
Albumin 2.0 (L) 3.5–5.2 g/dL
Calc total globulin 1.8 g/dL
Albumin/globulin ratio 1.1 (calc)
Total bilirubin 0.3 0.0–1.0 mg/dL
Alkaline phosphatase 102 (L) 116–450 IU/L
AST 36 0–37 IU/L
ALT 29 0–50 IU/L
Osmolality 254 (L) 275–295 mOsm/Kg
Amylase <10 (L) 28–100 U/L
Cholesterol, total 67 (L) 115–169 mg/dL
Triglycerides (fasting) 83 30–124 mg/dL
HDL 35 23–92 mg/dL
LDL calculated 15 mg/dL
Apolipoprotein B 49 (L) 55–140 mg/dL
Apolipoprotein A1 106 94–178 mg/dL
Vitamin A 0.17 (L) 0.20–0.50 mg/L
Vitamin D <7 (L) 20–120 ng/mL
Vitamin E 3.4 0.0–6.0 mg/L
Vitamin K 0.19 (L) 0.22–4.88 nmol/L
Zinc 49 (L) 60–120 μg/dL
Stool Patient value Reference range and units
Fecal occult blood Positive Negative
Fecal calprotectin 76 (H) ≤50 μg/g
Qualitative fecal fat Increased Normal
Helicobacter pylori antigen Negative Negative
AST = aspartate aminotransferase; ALT = alanine transaminase; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MCV = mean corpuscular volume; MCH = mean corpuscular hemoglobin; MCHC mean corpuscular hemoglobin concentration; MPV = mean platelet volume; RDW = red blood cell distribution width; RBC = red blood cell count; WBC = white blood cell count.

A picture of our patient’s growth chart demonstrating failure to thrive. His symptoms started at 2 months of age with eczema, emesis, and diarrhea with oily stools. His weight declined until he was admitted to the hospital at 7 months of age. He demonstrated normal weight gain 1 year after discharge.

He was admitted to the pediatric intensive care unit where his electrolyte derangements were corrected and feeds were initiated with an elemental formula due to concern for possible CMPA. Within 48 hours, his emesis and diarrhea resolved.

Further workup revealed decreased fat-soluble vitamins, elevated qualitative fecal fat (Table 1), and a complete abdominal ultrasound, which revealed normal anatomic structure with moderate ascites (in the setting of a serum albumin of 2.0 g/dL).

Histopathologic examination of esophagogastroduodenoscopy and flexible sigmoidoscopy revealed mild inflammation in the gastric body and increased epithelial cytoplasmic lipid droplets with preserved villous architecture in the duodenum (Figs. 2 and 3). The features of low fat-soluble vitamins, elevated fecal fat, and abnormal small bowel biopsies raised suspicion for abetalipoproteinemia, especially in the context of a blood smear showing acanthocytes, low apolipoprotein (apo) B level, and a low serum cholesterol (Table 1).

Duodenal mucosa with intact villous architecture and increased epithelial cytoplasmic lipid droplets (see arrows). Arrowhead corresponds to epithelium shown in Figure 3 at higher magnification (H&E staining, original magnification ×200). H&E = hematoxylin and eosin.
Compare normal duodenal epithelium on the lower aspect of the villus versus the abnormal epithelium with lipid droplets on the upper aspect. No increased intraepithelial lymphocytes are identified (H&E staining, original magnification ×600). H&E = hematoxylin and eosin.

He was started on a specialized low long chain triglyceride + high medium chain triglyceride formula containing cow’s milk protein, which was not tolerated and resulted in emesis and development of an erythematous facial rash. He was switched back to an elemental formula with medium chain triglyceride supplementation with resolution of symptoms. The patient was discharged after 2.5 weeks with improvement in weight by an average of 45 grams per day.

His genetic testing was ultimately not consistent with a diagnosis of abetalipoproteinemia and over the following year, his fat-soluble vitamin levels improved and remained stable following discontinuation of oral supplementation. He demonstrated good weight gain (Fig. 1) on an elemental formula and nondairy containing solid foods with transition to an elemental toddler formula at 12 months of age.


Our patient’s presentation of failure to thrive (FTT), oily stools, and laboratory abnormalities suggestive of fat malabsorption challenged us to consider a variety of differential diagnoses including inflammatory states, protein-losing enteropathy, congenital diarrheal disorders, inborn errors of metabolism, immunodeficiency, pancreatic insufficiency, abetalipoproteinemia, chylomicron retention disease, and CMPA. His diagnosis of severe CMPA was ultimately confirmed with resolution of his symptoms with introduction of an elemental formula followed by recrudescence of symptoms upon reintroduction of cow’s milk protein.

The differential diagnosis of FTT is quite diverse and broad. It can occur from a variety of both organic and nonorganic etiologies. This can include basic mechanisms of inadequate caloric intake, malabsorption, maldigestion secondary to diarrhea, or increased metabolic demand such as seen with congenital heart disease. Initial evaluation involves taking a detailed history, including feeding practices and formula preparation, identifying contributing factors and obtaining basic labs such as a complete blood count, comprehensive metabolic panel, magnesium, phosphorus, thyroid stimulating hormone, inflammatory markers, screens for inborn error of metabolism, and stool studies such as fecal elastase (3).

Abetalipoproteinemia is an autosomal recessive disorder in which a defect occurs in the formation of the microsomal triglyceride protein (MTP), which facilitates transfer of lipids onto apo B. Abnormal formation of MTP results in an absence of chylomicrons, low-density lipoproteins, and very-low-density lipoproteins leading to fat malabsorption, fat-soluble vitamin deficiency, and FTT (4). In addition to low apo B levels and evidence of fat malabsorption, the diagnosis requires confirmation by genetic testing. Ultimately, our patient’s genetic testing did not reveal defects in the MTP gene indicating he did not have abetalipoproteinemia, which was later confirmed by his ability to maintain normal fat-soluble vitamin levels following supplement discontinuation. His extreme presentation was most likely a result of severe malabsorption secondary to CMPA since he gained weight and maintained normal fat-soluble vitamin levels while on the amino acid formula.

CMPA is estimated to have an incidence of 2% to 7.5% in infants less than 1 year of age, and it can occur in both breastfed and formula fed infants (5). The treatment of CMPA involves removal of all cow’s milk protein from the child’s diet. For breastfed infants, this requires the mother to eliminate cow’s milk from her diet. For formula fed infants, this involves providing the infant with an alternative formula. North America Society for Pediatric Gastroenterology, Hepatology, and Nutrition recommend infants <6 months of age be fed an extensively hydrolyzed or an amino acid-based (elemental) formula (6). A trial of soy-based formula is not recommended in this age group due to the 10 percent risk of cross-reactivity; however, may be trialed in infants older than 6 months of age due to the poor palatability of the other formula options (6,7). Half of children with CMPA have resolution by 12 months of age and 80%–90% have resolution within 5 years (1). Resolution of cow’s milk protein-induced food protein-induced enterocolitis syndrome occurs at a median of 6.7 years in the United States (8). Children should be reevaluated every 6 months after 12 months of age to determine if the child is a candidate for reintroduction of cow’s milk (6).

Our patient’s clinical presentation and laboratory and histological findings demonstrated that CMPA can manifest as severe fat malabsorption, FTT, electrolyte abnormalities, and hemodynamic instability. This is due to the effect CMPA has on nutrient passage through the intestinal tract. Studies have shown evidence of jejunal mucosal damage resulting in rapid intestinal transit, which can lead to decreased nutrient and micronutrient absorption (9).

Even though CMPA can mimic other causes of malabsorption, it is important for pediatric medical care providers to be aware of such various presentations and have a high index of suspicion for CMPA as no specific symptom nor diagnostic test is pathognomonic for the diagnosis. In certain clinical scenarios, a trial with extensively hydrolyzed or elemental formula should be attempted with monitoring for symptom resolution. This approach can be beneficial to the patient prior to undertaking an extensive and invasive evaluation.


S.C. conceptualized and designed the study, drafted the initial article, reviewed and revised the article, and attests to the established criteria for authorship by the International Committee of Medical Journal Editors (ICMJE). A.S. collected data, carried out the initial analyses, reviewed and revised the article, and attests to the established criteria for authorship by the ICMJE. H.G. prepared the esophagogastroduodenoscopy histology slides and figures, reviewed and revised the article, and attests to the established criteria for authorship by the ICMJE. G.B. and A.C. coordinated and supervised data collection, critically reviewed the article, and attests to the established criteria for authorship by the ICMJE. All authors approved the final article as submitted and agree to be accountable for all aspects of the work.


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abetalipoproteinemia; cow's milk protein allergy; failure to thrive

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.