Vitamin C deficiency in children commonly presents with musculoskeletal symptoms such as gait disturbance, refusal to bear weight, and bone or joint pain. We aimed to identify features that could facilitate early diagnosis of scurvy and estimate the cost of care for patients with musculoskeletal symptoms related to scurvy.
We conducted a retrospective chart review of patients at a single site with diagnostic codes for vitamin C deficiency, ascorbic acid deficiency, or scurvy. Medical records were reviewed to identify characteristics including presenting symptoms, medical history, and diagnostic workup. The Pediatric Health Information System was used to estimate diagnostic and hospitalization costs for each patient.
We identified 47 patients with a diagnosis of scurvy, 49% of whom had a neurodevelopmental disorder. Sixteen of the 47 had musculoskeletal symptoms and were the focus of the cost analysis. Three of the 16 had moderate or severe malnutrition, and 3 had overweight or obesity. Six patients presented to an emergency department for care, 11 were managed inpatient, and 3 required critical care. Diagnostic workups included MRI, computed tomography, echocardiogram, endoscopy, lumbar puncture, and/or EEG. Across all patients evaluated, the cost of emergency department utilization, imaging studies, diagnostic procedures, and hospitalization totaled $470 144 (median $14 137 per patient).
Children across the BMI spectrum, particularly those with neurodevelopmental disorders, can develop vitamin C deficiency. Increased awareness of scurvy and its signs and symptoms, particularly musculoskeletal manifestations, may reduce severe disease, limit adverse effects related to unnecessary tests/treatments, and facilitate high-value care.
Vitamin C (ascorbic acid) cannot be synthesized by humans and is thus an essential nutrient from the diet. Vitamin C is essential for synthesis of collagen, nitric oxide, and catecholamines including epinephrine and norepinephrine.1,2 The constellation of symptoms caused by vitamin C deficiency, called scurvy, is often considered a “historic disease.”3 However, dietary restrictions in children with neurodevelopmental disorders like autism,4 eating disorders,5 or inflammatory bowel disease6 can lead to complete absence of vitamin C consumption and development of scurvy within 2 to 3 months.7,8 Over the past decade, case reports3,9–15 and case series16,17 have highlighted that scurvy remains relevant in modern medicine.
Symptoms of scurvy include fatigue, impaired wound healing, bleeding gums, and easy bruising. Physical exam may reveal petechiae, purpura, gingival hypertrophy and bleeding, and corkscrew hairs.8 In children with scurvy, musculoskeletal complaints (eg, pain, gait disturbance, refusal to bear weight) are often the most prominent symptom.7,8,15,17–19 Left untreated, severe vitamin C deficiency can cause pulmonary hypertension, cardiovascular collapse, and death,9,10,20–22 making its recognition and treatment critical. Treatment of scurvy can be initiated outpatient with oral or intramuscular ascorbic acid. If neither route is accepted, intravenous ascorbic acid can be given inpatient. Marked symptom improvement is commonly observed within 2 to 7 days of supplementation.8,15,17
Because vitamin C deficiency is an uncommon etiology for common musculoskeletal complaints, many providers do not routinely incorporate dietary history into their evaluations.17 Failure to include scurvy in the initial differential diagnosis can contribute to costly and invasive workups, including hospitalization and advanced diagnostic procedures to rule out inflammatory, infectious, autoimmune, and oncologic conditions with clinical overlap.8,23,24 Earlier recognition and treatment may help avoid some of this costly workup. In this study, we aimed to describe patient characteristics, radiographic findings, and costs associated with diagnostic workup in a cohort of patients with scurvy-related musculoskeletal symptoms.
Methods
We conducted a retrospective chart review of patients with an International Classification of Diseases, Ninth and 10th Revision (ICD-9/10), code for vitamin C deficiency, ascorbic acid deficiency, and/or scurvy from 2003 to 2022 at a single academic institution. Infants aged <1 year were excluded because of difficulty in determining presenting symptoms and the low risk because of adequate consumption of vitamin C in breast milk or infant formula.8 The protocol was deemed exempt by the institutional review board. Medical records were reviewed to identify presenting symptoms, past medical history, diet, and ascorbic acid level. Patients were excluded from further analysis if they did not meet at least 1 of the following criteria7 : (1) low plasma ascorbic acid level, (2) dietary history of limited to no vitamin C intake, or (3) documented clinical improvement with vitamin C supplementation.
For the subset of patients presenting with musculoskeletal symptoms, we obtained cost data using manual chart review and the Pediatric Health Information System, a comparative database of 49 US pediatric hospitals.25,26 The Pediatric Health Information System provides standardized unit costs calculated from charges and cost-to-charge ratios to limit interhospital variability.27,28 The number and type of diagnostic procedures, imaging studies, emergency department utilization, and hospitalization were extracted from medical records by 2 independent investigators for visits with a chief complaint related to musculoskeletal complaints within 6 months of scurvy diagnosis. Cost was calculated by multiplying the standardized cost for each unit by the total number for all patients in the cohort. We calculated the total cost for all patients combined, total cost for each patient, and the median per-patient cost. To determine whether imaging could facilitate an earlier scurvy diagnosis, available musculoskeletal imaging was reviewed independently by 2 pediatric radiologists.
Results
As an illustrative case from the chart review, a previously healthy 2.5-year-old female was admitted with 1 month of progressively worsening limp. Previous outpatient workup showed microcytic anemia (hemoglobin 9.7 g/dL), elevated erythrocyte sedimentation rate (31 mm per hour) with normal c-reactive protein, and normal radiographs of the hips and left tibia/fibula. All growth parameters were normal. She was evaluated by rheumatology, neurology, infectious disease, orthopedic surgery, and oncology. She had unremarkable cerebrospinal fluid testing and MRIs of the brain and spine. On day 2 of hospitalization, parents brought up concerns about her limited dietary intake that included no fruits, vegetables, or vitamins. Sedated MRI of the bilateral lower extremities showed symmetric abnormal marrow signal within the proximal and distal tibial/fibular and distal femoral metaphyses (Fig 1). The favored diagnosis was scurvy, and within 48 hours of vitamin C supplementation, the patient’s gait normalized.
Coronal (A) T1, (B) short τ inversion recovery, and (C) T1 fat-saturated postcontrast MRI of the legs showing decreased T1 signal (green arrows), symmetric increased short τ inversion recovery signal (yellow arrows), and enhancement (blue arrows) in bilateral distal femoral metaphyses, and proximal and distal tibial metaphyses. Images also revealed bright short τ inversion recovery subperiosteal signal and enhancement (red and orange arrows).
Coronal (A) T1, (B) short τ inversion recovery, and (C) T1 fat-saturated postcontrast MRI of the legs showing decreased T1 signal (green arrows), symmetric increased short τ inversion recovery signal (yellow arrows), and enhancement (blue arrows) in bilateral distal femoral metaphyses, and proximal and distal tibial metaphyses. Images also revealed bright short τ inversion recovery subperiosteal signal and enhancement (red and orange arrows).
Of the 56 patients identified by ICD-9/10, codes, 47 met the above criteria for diagnosis of scurvy (Supplemental Table 3), 74% (n = 35) confirmed by low plasma ascorbic acid levels. Age at diagnosis ranged from 13 months to 25 years and 36% (n = 17) were female. Forty-nine percent (n = 23) had a neurodevelopmental diagnosis, including autism spectrum disorder (n = 18) or other developmental disorder (n = 5) such as cerebral palsy. At the time of diagnosis, 26% (n = 12) had severe malnutrition (BMI z score ≤−3) and 13% (n = 8) had obesity (BMI ≥95 percentile). Other past medical history included inflammatory bowel disease, eosinophilic-associated gastrointestinal diseases, hematologic conditions, and multiple food allergies. One patient was postbariatric surgery. Three patients had recently immigrated from locations with limited access to fruits and vegetables. Presenting symptoms included musculoskeletal pain or gait disturbance (34%, n = 16), gingival bleeding or hypertrophy (17%, n = 8), bruising (15%, n = 7), and/or petechiae (6%, n = 3).
The subset of 16 patients presenting with musculoskeletal symptoms (including limp, joint or bone pain, refusal to bear weight) (Supplemental Table 4) were the focus of additional cost and radiologic study. Six of these patients presented to the emergency department at least once. Eleven patients were managed inpatient (median 6.5 days, interquartile range 5 to 16 days). Two of the 12 had cardiac arrest during anesthesia induction for diagnostic procedures, subsequently attributed to vitamin C deficiency-induced pulmonary hypertension, and required prolonged hospitalizations of 41 and 91 days for acute care and rehabilitation.20 One patient was hospitalized twice. A total of 18 MRIs (including brain, spine, and/or lower extremities) were obtained in 9 patients and 4 patients had at least 1 computed tomography scan (head, chest, and/or abdomen; Supplemental Table 4). Additional workup included echocardiogram (n = 7), endoscopy (n = 3), lumbar puncture (n = 3), and EEG (n = 1). Four patients required sedation for imaging or other procedures (Table 1). Diagnostic testing and care for the 16 patients with musculoskeletal symptoms because of scurvy were associated with at least $470 144 (median per patient $14 137; range $0–193 217) (Table 1, Supplemental Table 4).
Costs of Diagnostic and Imaging Studies, as Well as Emergency Department Utilization and Hospitalization, Extracted by CPT Code From the Pediatric Health Information System
| Procedure/Study | Cost | Number | Total |
|---|---|---|---|
| X-ray hips | $104.19 | 4 | $416.76 |
| X-ray lower extremity | $95.91 | 9 | $863.19 |
| X-ray foot | $86.10 | 1 | $86.10 |
| X-ray tibia/fibula | $88.04 | 1 | $88.04 |
| X-ray spine | $91.26 | 4 | $365.04 |
| X-ray abdomen | $97.39 | 2 | $194.78 |
| MRI brain | $427.18 | 9 | $3844.62 |
| MRI spine | $1096.50 | 4 | $4386.00 |
| MRI lower extremity | $668.09 | 2 | $1336.18 |
| MRI hips | $452.82 | 1 | $452.82 |
| MRI chest/abdomen/pelvis | $1323.34 | 2 | $2646.68 |
| CT head | $185.48 | 3 | $556.44 |
| CT chest | $231.94 | 1 | $231.94 |
| CT abdomen | $376.36 | 1 | $376.36 |
| EEG | $247.04 | 1 | $247.04 |
| Endoscopy | $602.31 | 3 | $1806.92 |
| Echocardiogram | $419.57 | 7 | $2936.99 |
| Imaging sedation | $146.00 | 5 | $730.00 |
| Lumbar puncture | $783.67 | 3 | $2351.01 |
| Emergency department | $424.19 | 9 | $3817.68 |
| Hospital floor per d | $1933.96 | 177 | $342 310.92 |
| Critical care per d | $3228.98 | 31 | $100 098.50 |
| Total | — | — | $470 144.02 |
| Median cost per patient | — | — | $14 136.70 |
| Procedure/Study | Cost | Number | Total |
|---|---|---|---|
| X-ray hips | $104.19 | 4 | $416.76 |
| X-ray lower extremity | $95.91 | 9 | $863.19 |
| X-ray foot | $86.10 | 1 | $86.10 |
| X-ray tibia/fibula | $88.04 | 1 | $88.04 |
| X-ray spine | $91.26 | 4 | $365.04 |
| X-ray abdomen | $97.39 | 2 | $194.78 |
| MRI brain | $427.18 | 9 | $3844.62 |
| MRI spine | $1096.50 | 4 | $4386.00 |
| MRI lower extremity | $668.09 | 2 | $1336.18 |
| MRI hips | $452.82 | 1 | $452.82 |
| MRI chest/abdomen/pelvis | $1323.34 | 2 | $2646.68 |
| CT head | $185.48 | 3 | $556.44 |
| CT chest | $231.94 | 1 | $231.94 |
| CT abdomen | $376.36 | 1 | $376.36 |
| EEG | $247.04 | 1 | $247.04 |
| Endoscopy | $602.31 | 3 | $1806.92 |
| Echocardiogram | $419.57 | 7 | $2936.99 |
| Imaging sedation | $146.00 | 5 | $730.00 |
| Lumbar puncture | $783.67 | 3 | $2351.01 |
| Emergency department | $424.19 | 9 | $3817.68 |
| Hospital floor per d | $1933.96 | 177 | $342 310.92 |
| Critical care per d | $3228.98 | 31 | $100 098.50 |
| Total | — | — | $470 144.02 |
| Median cost per patient | — | — | $14 136.70 |
CPT, Current Procedural Terminology; CT, computed tomography.
Eleven of 16 patients had radiographs of the lower extremities and/or hips. One patient had osteopenia with a dense epiphyseal ring (Wimberger rim) in the distal femur. No patients demonstrated the historically described sclerotic or lucent metaphyseal band (white line of Frankel and Trummerfeld zone, respectively) or metaphyseal (Pelkan) spur.16,17 The most common abnormalities on lower extremity MRI were symmetric metaphyseal bone marrow and soft tissue edema, periosteal reaction, and subperiosteal fluid (Fig 1). Differential diagnoses proposed by the radiologist in the original interpretation were chronic multifocal osteomyelitis, leukemia, and Langerhans cell histiocytosis. Diagnosis of nutritional deficiency was suggested on 1 MRI interpretation.
Discussion
We highlight scurvy as an important inclusion in the differential diagnosis for patients with restricted dietary intake presenting with musculoskeletal pain, limp, and/or refusal to bear weight. Vitamin C deficiency may impact up to 7% of the US population.29,30 Our cohort redemonstrates that many children lack traditional scurvy symptoms such as bleeding gums or petechiae, and may not have classic radiographic signs.8,13 On MRI, bilateral, symmetric long bone metaphyseal marrow edema and enhancement with subperiosteal collections and adjacent myositis and soft tissue edema may be early clues to a scurvy diagnosis.8,16
Similar to previous reports,13,15,18,23,24 we show an association of scurvy musculoskeletal symptoms with expensive diagnostic workups that include radiation and sedation exposure. Obtaining a brief dietary history and initiating vitamin C supplementation early can support high-value care,8 defined as maximizing quality and limiting costs.31 We suggest that providers screen children with restricted intake across the BMI spectrum for adequate vitamin C intake and consider referral to a nutrition specialist for a complete growth/micronutrient workup as needed (Table 2).
Vitamin C-Related Recommendations for Providers Evaluating Children With Musculoskeletal Symptoms of Unclear Etiology
| Outpatient Provider | Inpatient Provider | |
|---|---|---|
| Dietary evaluation | 1-question screener: “Does the child eat something from each food group; for example, fruits, vegetables, proteins, and grains?” If minimal to no fruits/vegetables (including juice) and no fortified oral nutrition drink or vitamin: 1. Obtain an ascorbic acid level. 2. Consider referral/consult to nutrition specialist for comprehensive assessment of growth, eating behaviors, and micronutrient status (eg, dietitian, gastroenterologist, nutrition physician, feeding therapist). | |
| Treatment initiation | • Empirically start (ie, before the ascorbic level comes back) oral (tablet, powder, liquid, gummy) or intramuscular ascorbic acid 300 mg daily + consider multivitamin daily while pursuing additional workup. | • Empirically start (ie, before the ascorbic level comes back) oral, intramuscular, or intravenous ascorbic acid 300 mg daily + consider multivitamin daily and monitor for symptom improvement while pursuing additional workup per clinical judgment. • Consider delaying nonurgent anesthesia exposure to reduce risks of unrecognized pulmonary hypertension.20 |
| If Vitamin C deficiency is confirmed, typical treatment is 300 mg × 1 wk, then 100 mg × 1–3 mo by any reliable route. | ||
| Radiology considerations | • If significant dietary restriction is present, the provider ordering the imaging should include this in the indications/order comments to provide the radiologist appropriate context. • Classic findings of scurvy on plain radiographs (Wimberger rim, white line of Frankel, Tummerfeld zone, metaphyseal Pelkan spur) may not be present. • Consider scurvy when MRI, performed for nonspecific lower-extremity symptoms, reveals highly symmetric metaphyseal bone marrow edema. | |
| Outpatient Provider | Inpatient Provider | |
|---|---|---|
| Dietary evaluation | 1-question screener: “Does the child eat something from each food group; for example, fruits, vegetables, proteins, and grains?” If minimal to no fruits/vegetables (including juice) and no fortified oral nutrition drink or vitamin: 1. Obtain an ascorbic acid level. 2. Consider referral/consult to nutrition specialist for comprehensive assessment of growth, eating behaviors, and micronutrient status (eg, dietitian, gastroenterologist, nutrition physician, feeding therapist). | |
| Treatment initiation | • Empirically start (ie, before the ascorbic level comes back) oral (tablet, powder, liquid, gummy) or intramuscular ascorbic acid 300 mg daily + consider multivitamin daily while pursuing additional workup. | • Empirically start (ie, before the ascorbic level comes back) oral, intramuscular, or intravenous ascorbic acid 300 mg daily + consider multivitamin daily and monitor for symptom improvement while pursuing additional workup per clinical judgment. • Consider delaying nonurgent anesthesia exposure to reduce risks of unrecognized pulmonary hypertension.20 |
| If Vitamin C deficiency is confirmed, typical treatment is 300 mg × 1 wk, then 100 mg × 1–3 mo by any reliable route. | ||
| Radiology considerations | • If significant dietary restriction is present, the provider ordering the imaging should include this in the indications/order comments to provide the radiologist appropriate context. • Classic findings of scurvy on plain radiographs (Wimberger rim, white line of Frankel, Tummerfeld zone, metaphyseal Pelkan spur) may not be present. • Consider scurvy when MRI, performed for nonspecific lower-extremity symptoms, reveals highly symmetric metaphyseal bone marrow edema. | |
Although our study describes a relatively large cohort of patients with vitamin C deficiency, it is not without limitations. Our cost estimates did not include laboratory studies, physician charges, or wasted resources. We also did not account for nonmedical expenses associated with seeking care such as lost wages, transportation, or meals.32–34 In addition, we did not have a comparison group to determine how costs may have been impacted by expedited diagnosis. Finally, although plasma ascorbic acid level is the most common diagnostic test,1,7 it can be falsely elevated because of recent ingestion of vitamin C from foods or supplements, or falsely low if the blood sample is exposed to light or allowed to thaw during transportation.35 Where possible, we confirmed the diagnosis of vitamin C deficiency by review of dietary records.
In conclusion, we show that children across the BMI spectrum, particularly those with neurodevelopmental disorders, can be at risk for vitamin C deficiency. Scurvy in children often presents with musculoskeletal complaints and without the classic physical exam or radiographic findings. We propose a brief dietary screen and timing for empirical supplementation that may facilitate high-value care.
Acknowledgment
We thank Mark Gritz, PhD, for advice and guidance.
Dr Gilley conceived and designed the study, performed chart review, led data collection, analysis, and interpretation, conducted cost analysis, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Ta performed chart review, contributed to data collection and interpretation, and critically reviewed and revised the manuscript; Drs Pryor and Fenton performed clinical image and chart review, conducted analysis and interpretation of data, and critically reviewed and revised the manuscript; Drs Roper and Erickson performed chart review, conducted analysis and interpretation of data, and critically reviewed and revised the manuscript; Drs Tchou and Cotter gathered cost information, conducted analysis and interpretation of data, and critically reviewed and revised the manuscript; Dr Moore supervised the conceptualization and design of the study, supervised data collection, analysis, and interpretation, drafted the initial manuscript, and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
A deidentified data set generated during and/or analyzed during the current study is available from the corresponding author on reasonable request.
FUNDING: Dr Moore received support from the Children’s Hospital Colorado Research Institute Research Scholar Award for this work. Dr Tchou was in part funded via a PEDSnet Scholars Training Program grant, a national faculty development program that trains individuals in health systems science. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations. The funders had no role in the design or conduct of this study.
CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest relevant to this article to disclose.
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