One week before presenting to the hospital, a 20-year-old man with Landau–Kleffner Syndrome, a disorder characterized by loss of higher cortical functioning similar to autism spectrum disorder, developed acute onset skin changes, pallor, and fatigue. His primary care doctor noted bruising and petechiae overlying his bilateral upper and lower extremities. Laboratories were drawn, including a complete cell count prothrombin time and international normalized ratio (INR), all of which returned unremarkable (white blood cells 6.7 k/mm3, platelets 283 mg/dL, INR 1.1, hematocrit 33.7%).

Over the next several days, the patient developed gross hematuria and stopped walking, subsequently presenting to the emergency department for further evaluation. There, he was found to have persistent skin findings along with gum bleeding. He underwent an extensive laboratory evaluation notable for a hematocrit of 25.3% with a mean corpuscular volume of 83.5 fL per cell, an elevated C-reactive protein of 7 mg/L and erythrocyte sedimentation rate of 75 mm/hour, an elevated unconjugated bilirubin at 2.7 mg/dL, and a slightly decreased albumin at 3.6 g/dL. Raw absolute reticulocyte count was 0.142 M/mm3, and hematocrit-corrected reticulocyte count was 2.5%. Peripheral smear was notable for hypochromasia, polychromasia, Dohle bodies, and giant platelets. Haptoglobin was 264 mg/dL, and platelet count was 301 000 per μL. D-Dimer was elevated at 4.1 μg/mL, whereas prothrombin time, INR, partial thromboplastin time, and lactate dehydrogenase were within normal limits. Direct antiglobulin test was negative. Urine microscopy demonstrated 0 to 2 red blood cells per high powered field with positive urobilinogen despite no gross hematuria.

The patient was admitted with a presumptive diagnosis of hemolytic anemia of unknown etiology. During the first 24 hours of admission, he underwent testing to assess for underlying causes of hemolysis, including glucose-6-phosphate dehydrogenase deficiency, hereditary spherocytosis, and infectious agents such as Mycoplasma and Epstein-Barr virus. Abdominal ultrasound showed no splenomegaly, and lower extremity Doppler ruled out deep venous thrombosis. A lower extremity MRI was obtained to better visualize his soft tissues on day 3. This showed subcutaneous and fascial edema bilaterally, suggestive of a mild myositis in both calves. The diagnosis of vitamin C deficiency, or scurvy, was suggested by the radiologist.

Vitamin C deficiency had been considered at the time the MRI was ordered, and a vitamin C level was obtained the day before the MRI. The level did not result until several days later (turnaround time 5–7 days at this institution). After increased suspicion from the MRI, a nutritional history was obtained, revealing that the patient’s diet primarily consisted of ham and cheese croissants, macaroni and cheese, tater tots, and wheat bread, with the infrequent serving of green beans. He did not eat any fruits or other vegetables and drank 2 to 3 cans of soda and 1 to 2 cups of apple juice daily.

The patient’s vitamin C level was ultimately undetectable. Because of a significant degree of deconditioning secondary to his delay in diagnosis of scurvy, he required a prolonged inpatient stay of 21 days, including inpatient rehabilitation. Highlighted by this case is how neglected pieces of a patient history led to unnecessary testing, increased hospital expenditures, and a prolonged recovery of illness for a patient.

Historically, scurvy is associated with pirates and cross-Atlantic sailings in the 17th and 18th centuries. Although often found in patients with advanced chronic diseases and cancers,13  vitamin C deficiency remains underrecognized and underdiagnosed in developed nations.4,5  The root cause for vitamin C deficiency is poor nutrition. Severely restrictive eating patterns in children with developmental and behavioral delays puts this population at unique risk for the development of an otherwise rare condition.69 

The most specific clinical features of scurvy are cutaneous manifestations such as hyperkeratosis, perifollicular hemorrhage, corkscrew hairs, and purpura. Gingival changes such as bleeding, friability, and necrosis can also be seen. Nonspecific symptoms include myalgias, arthralgias, weakness, fatigue, and dyspnea (classically due to anemia). Although the underlying cause is not well understood, a nonspecific anemia with an elevated reticulocyte count is often found. Vitamin C is an important cofactor for erythropoiesis, and its deficiency may contribute to the anemia10 ; vascular fragility leading to acute blood loss with subcutaneous hemorrhage also may play a role.11  Other cell lines are usually normal. Elevation in erythrocyte sedimentation rate can be seen, and erythrocyte hyperplasia is seen on bone marrow biopsy.12  Although imaging is not usually used to diagnose scurvy, images are often obtained before recognition of vitamin C deficiency. Typically, nonspecific findings on MRI include cortical sclerosis with metaphyseal lucency and a surrounding edema or periosteal reaction.13,14 

A nutritional history was not obtained on our patient at the time of presentation despite a known severe developmental delay. This resulted in an extensive laboratory evaluation, multiple modalities of imaging, multiple subspecialty consultations, and a prolonged, 3-week hospital stay.

We reviewed cases of patients diagnosed with vitamin C deficiency at a freestanding children’s hospital between 2016 and 2018. All cases with undetectable vitamin C levels were identified. We excluded any case involving a patient undergoing treatment of an oncologic diagnosis, because patients with cancer frequently experience vitamin C deficiency and are regularly screened for its development.15  This left 5 cases of nutritionally related vitamin C deficiency. Cases were reviewed for initial presenting symptoms, diagnostic evaluation, consulting services, time to dietary history, time to first vitamin C level, and case resolution (Table 1).

TABLE 1

Case Descriptions of Patient Diagnosed With Vitamin C Deficiency

PatientAge, ySexPreexisting DiagnosesPresentationNo. Days Until Nutrition History TakenTime to Vitamin C Level DrawnInitial Vitamin C Level, mg/dLAdmission Hematocrit, %Imaging ObtainedConsultsHospital Length of Stay, d
1a 20 Male Landau–Kleffner Syndrome, prematurity Bruising, petechiae, corkscrew hairs, fatigue, hematuria, gum bleeding, fever <0.1 25.3 Lower extremity XR (×2), pelvis XR, abdominal ultrasound, lower extremity Doppler, MRI Hematology, rheumatology, rehab medicine 21 
15 Male Severe autism spectrum disorder, restrictive eating Pallor, fatigue, decreased PO <0.1 18.5 None None 
Male Nonspecified behavioral challenges Bilateral knee pain, edema, refusal to bear wt, recent history of necrotic peridontal disease <0.1 26.7 XR, MRI Hematology, rheumatology, orthopedics, infectious disease 
17 Male High functioning Autism Left leg discoloration, edema, posterior knee pain, perifollicular petechiae, corkscrew hairs <0.1 18.3 CT angiography, MRI, ultrasound Orthopedics 
Male Nonverbal autism Left knee pain and swelling, fevers, refusal to bear wt <0.1 33.5 Ultrasound, XR, MR-HASTE, MRI Orthopedics, infectious disease, rheumatology, hematology-oncology 
PatientAge, ySexPreexisting DiagnosesPresentationNo. Days Until Nutrition History TakenTime to Vitamin C Level DrawnInitial Vitamin C Level, mg/dLAdmission Hematocrit, %Imaging ObtainedConsultsHospital Length of Stay, d
1a 20 Male Landau–Kleffner Syndrome, prematurity Bruising, petechiae, corkscrew hairs, fatigue, hematuria, gum bleeding, fever <0.1 25.3 Lower extremity XR (×2), pelvis XR, abdominal ultrasound, lower extremity Doppler, MRI Hematology, rheumatology, rehab medicine 21 
15 Male Severe autism spectrum disorder, restrictive eating Pallor, fatigue, decreased PO <0.1 18.5 None None 
Male Nonspecified behavioral challenges Bilateral knee pain, edema, refusal to bear wt, recent history of necrotic peridontal disease <0.1 26.7 XR, MRI Hematology, rheumatology, orthopedics, infectious disease 
17 Male High functioning Autism Left leg discoloration, edema, posterior knee pain, perifollicular petechiae, corkscrew hairs <0.1 18.3 CT angiography, MRI, ultrasound Orthopedics 
Male Nonverbal autism Left knee pain and swelling, fevers, refusal to bear wt <0.1 33.5 Ultrasound, XR, MR-HASTE, MRI Orthopedics, infectious disease, rheumatology, hematology-oncology 

CT, computed tomography; MR-HASTE, magnetic resonance–half-Fourier acquisition single shot turbo spin echo; PO, oral intake; XR, radiograph.

a

Featured case reported in the text.

All 5 patients had recognized developmental or behavioral abnormalities, and yet half had a delay in obtaining an adequate nutrition history. Patient 3 (Table 1), who presented with significant anemia and history of periodontal bleeding, did not have a vitamin C level drawn until 4 days into hospitalization. He had 4 subspecialty consults and underwent a bone marrow biopsy before a dietary history prompted obtaining a vitamin C level.

Two patients from Table 1 had early vitamin C levels drawn, and both had nutrition histories documented in their admission note. Patient 2 actually had “restrictive eating” listed as a diagnosis in his medical chart, prompting referral to hematology clinic from his primary care doctor and then admission. Patient 4 presented with skin changes classic for vitamin C deficiency, including perifollicular petechiae and corkscrew hairs. A dietary history and vitamin C level were obtained on presentation, yet, despite this, he still underwent an extensive evaluation including an MRI and computed tomography angiography of his left leg to evaluate for possible deep venous thrombosis with additional subspecialty consults.

Timing of dietary history had significant implications on length of hospital stay. The 2 patients with nutrition histories taken at the time of admission had much shorter length of stays (3 nights), whereas the other 3 patients had stays ranging from 1 to 3 weeks. Adding a vitamin C level to the initial set of diagnostic laboratories (in the emergency department or clinic) could help to prevent further unnecessary testing and imaging. Prolonged hospitalizations lead to increased costs to families and the health care system as well as much potential harm, evidenced by the imaging with radiation exposure, biopsies with anesthesia exposure, and laboratory studies. Most of our patients presented with hallmark changes such as perifollicular hemorrhage and corkscrew hairs, but it was the recognition of restrictive eating patterns that led to more rapidly obtaining the dietary history and, ultimately, faster diagnoses and shorter hospital stays.

For patients with known behavioral or developmental delays presenting with nondescript symptoms, obtaining a dietary history on initial presentation could inform a more targeted laboratory and imaging workup. Dietary history incurs 0 financial cost and is a minimal time burden. Because the turnaround time for vitamin C levels at many intuitions is often several days, a high index of suspicion must be maintained to avoid unnecessary testing and consults. Obtaining a level with laboratories at presentation to the hospital may prevent a shotgun approach or repeat testing, as seen in patient 5, who had a repeat MRI 5 days into his admission. As seen in patients 2 and 4, when considered early in the hospital course, much of the testing may be avoided. We would propose, when scurvy is suspected, that supplementation with ascorbic acid may be initiated without confirmatory vitamin C levels. In addition, having a vitamin C level resulted should not prolong a hospitalization if the child clinically is stable and improving on supplementation.

Because vitamin C deficiency remains infrequent and children often present with diverse concerning symptoms, there may still be benefit in sending initial confirmatory testing. However, trending vitamin C levels has limited value for the patient if they are improving clinically. Treatment doses of ascorbic acid range from 50 to 200 mg per day, depending on the child’s age and size. Toxicity is typically not seen until >2000 mg per day, which is well under what any of our patients required to reach normal vitamin C levels. Although some of our patients had vitamin C levels repeated in outpatient clinics, no changes were made to dosing supplementation based off the levels. Similar to trending vitamin D levels in children, trending vitamin C levels may not be indicated.

Providers should maintain a high index of suspicion for nutritional deficiencies in children with developmental or behavioral delays. Early recognition of restrictive eating patterns through a timely dietary history may spare children delayed diagnosis, extensive and expensive laboratory and imaging workups, invasive testing, and prolonged hospital stays.

Drs Gandhi and McDaniel conceptualized and designed the study, drafted the initial manuscript, reviewed and revised the manuscript, and approved the final manuscript as submitted.

FUNDING: No external funding.

1
Hoffman
FA
.
Micronutrient requirements of cancer patients
.
Cancer
.
1985
;
55
(
suppl 1
):
295
300
2
Mahdavi
R
,
Faramarzi
E
,
Seyedrezazadeh
E
,
Mohammad-Zadeh
M
,
Pourmoghaddam
M
.
Evaluation of oxidative stress, antioxidant status and serum vitamin C levels in cancer patients
.
Biol Trace Elem Res
.
2009
;
130
(
1
):
1
6
3
Mayland
CR
,
Bennett
MI
,
Allan
K
.
Vitamin C deficiency in cancer patients
.
Palliat Med
.
2005
;
19
(
1
):
17
20
4
Carpenter
KJ
.
The History of Scurvy and Vitamin C
.
Cambridge, NY
:
Cambridge University Press
;
1986
5
Agarwal
A
,
Shaharyar
A
,
Kumar
A
,
Bhat
MS
,
Mishra
M
.
Scurvy in pediatric age group - a disease often forgotten?
J Clin Orthop Trauma
.
2015
;
6
(
2
):
101
107
6
Kazandjieva
J
,
Antonov
D
,
Kamarashev
J
,
Tsankov
N
.
Acrally distributed dermatoses: vascular dermatoses (purpura and vasculitis)
.
Clin Dermatol
.
2017
;
35
(
1
):
68
80
7
Centers for Disease Control and Prevention
.
Data & statistics on autism spectrum disorder
.
2018
.
Available at: https://www.cdc.gov/ncbddd/autism/data.html. Accessed October 1, 2018
8
Bandini
LG
,
Anderson
SE
,
Curtin
C
, et al
.
Food selectivity in children with autism spectrum disorders and typically developing children
.
J Pediatr
.
2010
;
157
(
2
):
259
264
9
Cermak
SA
,
Curtin
C
,
Bandini
LG
.
Food selectivity and sensory sensitivity in children with autism spectrum disorders
.
J Am Diet Assoc
.
2010
;
110
(
2
):
238
246
10
Cox
EV
.
The anemia of scurvy
.
Vitam Horm
.
1968
;
26
:
635
652
11
Reuler
JB
,
Broudy
VC
,
Cooney
TG
.
Adult scurvy
.
JAMA
.
1985
;
253
(
6
):
805
807
12
Hirschmann
JV
,
Raugi
GJ
.
Adult scurvy
.
J Am Acad Dermatol
.
1999
;
41
(
6
):
895
906; quiz 907–10
13
Golriz
F
,
Donnelly
LF
,
Devaraj
S
,
Krishnamurthy
R
.
Modern American scurvy - experience with vitamin C deficiency at a large children’s hospital
.
Pediatr Radiol
.
2017
;
47
(
2
):
214
220
14
Lucarelli
J
,
Pappas
D
,
Welchons
L
,
Augustyn
M
.
Autism spectrum disorder and avoidant/restrictive food intake disorder
.
J Dev Behav Pediatr
.
2017
;
38
(
1
):
79
80
15
Klimant
E
,
Wright
H
,
Rubin
D
,
Seely
D
,
Markman
M
.
Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach
.
Curr Oncol
.
2018
;
25
(
2
):
139
148

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.