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EXPERIENCE & REASON |
a Departments of Neurology
b Pediatrics, Morgan Stanley Children's Hospital of New York and the Neurological Institute of New York, Columbia University Medical Center, New York, New York
ABSTRACT
The North American epidemic of overeating, combined with a sedentary lifestyle, has led to a growing prevalence of obesity, diabetes, and the "metabolic syndrome" in children. Excessive caloric intake does not imply adequate nutrition, and vitamin-deficiency syndromes still occur in some American children. Here we describe cases of scurvy and vitamin D deficiency in 2 children with cognitive disorders. Thorough dietary histories suggested the diagnosis in each patient and, had they been obtained at presentation, would likely have obviated invasive diagnostic workup, unnecessary stress to the patients and their families, and significant functional disability. Overnutrition and malnutrition may coexist, particularly among those with abnormal cognition or autistic spectrum disorders. Classic nutritional deficiencies must not be omitted from the differential diagnosis. A comprehensive dietary history and screening for vitamin deficiencies in at-risk children are important aspects of preventive health care and are essential for prompt diagnosis and treatment.
Key Words: scurvy • autistic spectrum disorder • vitamin D deficiency • malnutrition • hypocalcemia
More than 50% of adults in the United States are overweight or obese, and similar trends are emerging in children. Suggested risk factors for development of pediatric obesity include lack of physical activity, excessive television/video viewing, sugar-sweetened drink consumption, large portion sizes, consumption of low amounts of fruits and vegetables, and not breastfeeding.1 Figures from the Centers for Disease Control and Prevention in 2002 indicated increasing rates of obesity, with 16.1% of 12- to 19-year-old children being overweight (defined as those 
95th percentile of the gender-specific BMI-for-age growth chart) and an additional 14.8% of the same population designated as at risk for becoming overweight; this trend was only slightly more common in boys than girls.2 A review of obese children and adolescents presenting to our hospital's clinics revealed high rates of hypertension (11%–19%), hypercholesterolemia (18%), impaired glucose tolerance (7%), and metabolic syndrome (14%).3
Excess caloric intake does not imply adequate nutrition or exclude vitamin deficiencies, which, although seemingly rare, still occur in urban and suburban communities.4–6 Although Talbot7 contended in 1963 in Pediatrics that in daily practice, "psychologic malnutrition" (a term coined for poorly understood behavioral disorders) would replace easily treatable diseases such as scurvy and rickets, 2 cases of symptomatic vitamin deficiency that presented to our neurologic consultation service within 1 week suggest that certain pediatric neuropsychiatric disorders have allowed these diseases to persist, often going unrecognized for prolonged periods of time. Here we review these cases and recent studies that have suggested that, within certain populations, perhaps we should focus on dietary deficiencies as much as excess.
CASE REPORTS
Case1.
A 5-year-old white boy from suburban New York City presented with listlessness, behavioral regression, and an antalgic gait. He was diagnosed with pervasive developmental disorder at 18 months of age. He had no physical limitations and was highly skilled in age-appropriate video games. His socialization improved after enrolling in school at 5 years of age. His verbal expression remained limited; he spoke in single words or brief phrases. Six months before admission, he was enrolled in a special school where his program included physical, occupational, and speech therapy and applied behavioral analysis.
Six weeks before admission, his teachers reported diminished energy and withdrawal. One week later, he was less playful and lost interest in climbing and running. While ascending a slight incline, the patient fell onto his buttocks, cried inconsolably, and walked with a right-sided limp thereafter. Over the next few days, he complained of right leg pains and frequently asked to be carried. His behavior regressed further, and he constantly requested a pacifier. He lost interest in his favorite computer games. He stopped talking and communicated with inarticulate groans and by pointing at desired objects. He subsequently stopped walking and took to bed.
His orthopedist and neurologist found a limping antalgic gait; his regressive behavior was attributed to a nonspecific musculoskeletal disorder.
Because of concern that he would regress further as an inpatient, hospitalization was deferred. Outpatient workup revealed normal blood chemistry and peripheral blood counts. His erythrocyte sedimentation rate was 20 mm/hour (reference range: 0–15 mm/hour) at the initial evaluation and 44 mm/hour 1 week later. Radiographs revealed a questionable right fibular fracture that was not confirmed on a technetium 99m bone scan. He had anorexia and lost 8 pounds over the next 3 weeks.
The patient was admitted to our center for evaluation of worsening pain, fatigue, and failure to thrive. He was bedbound at the time of admission.
He took no medications. His mother and 12-year-old sister both had learning difficulties; a maternal uncle had features of autism. The family declined genetic investigation. The patient's maternal grandfather died of brain biopsy–proven Creutzfeldt-Jakob disease at the age of 60.
Examination showed a slender boy lying in bed, sucking on his pacifier, whose hips and knees were always flexed. His weight was 15 kg (5th percentile), height was 105 cm (25th percentile), and BMI was 13.6 kg/m2 (<5th percentile). He was drowsy but easily roused and remained awake through the examination. There was a nonblanching micropapular petechial rash on the extensor surfaces of his left arm and right thigh, and gradually enlarging ecchymoses were noted at sites of attempted blood draws. He had no gingival bleeding. Each of his 3 middle fingers had horizontal subungual linear ecchymoses, each equidistant from the nail bed. No finger biting had been witnessed by his family. His hair was normal. Attempts to passively extend his knees and hips provoked active flexion of his hips and knees and inarticulate cries. There were no joint effusions, crepitus, or enlargement. Muscle palpation and range-of-motion testing of his ankles, arms, neck, hands, and fingers were unremarkable. He had limited spinal flexion and maintained an extended posture. Examination of his cranial nerves, upper extremities, reflexes, and coordination was unremarkable, as was the general medical examination. A diffuse musculoskeletal problem was suspected, with the differential diagnosis including juvenile rheumatoid arthritis, hematologic malignancy, and Goldbloom syndrome. An exhaustive diagnostic workup was pursued. Table 1 summarizes the patient's serial laboratory data.
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On the ninth hospital day, his vitamin C level (from serum collected on admission) was reported as undetectable, which confirmed the diagnosis of scurvy. The assay was suggested after review of the bone marrow biopsy and observation of his progressive ecchymoses and gingival bleeding, which began during hospitalization.
Retrospective review of his dietary history was revealing. The patient was breastfed for the first 6 months and supplemented with nocturnal infant formula once fortified infant foods were introduced. By 12 months of age he ate table foods including pasta and corn, but he never liked cereals or other common "finger foods." He had limited citrus fruits in his diet but ate bananas and was supplemented with multivitamins until 2 years of age. At this point his dietary behavior changed, and he progressively restricted his diet. By 3 years of age, his daily diet consisted only of dry Honeycomb cereal at breakfast, strawberry yogurt for lunch, plus Goldfish crackers, Ritz crackers, and Ritz cheese and cracker sandwiches as snacks. For dinner he only ate generic grocery store brand ice cream (vanilla plus chocolate sauce or vanilla and chocolate combination), served in a small Dixie-style cup. Once weekly he ate garlic and marinara pasta at a local restaurant. By 1 year before admission he no longer ate Honeycomb cereal but was substituting crackers for breakfast. Six months later he stopped eating the restaurant pasta. Unknown to his parents, he did not eat the yogurt packed for his lunch once he enrolled in school 6 months before admission, and he refused to eat it on weekends thereafter. Thus, for 6 months before admission his diet was restricted to crackers, ice cream, and water.
Discussion
References exist in ancient literature, but the first well-described cases of scurvy date to the era of oceanic (as contrasted to coastal) exploration by sailing vessels when sailors had a restricted diet that excluded perishables (including citrus fruits) for periods of months to years. Historical accounts of those afflicted with scurvy and the first attempts at treatment bear a brief review centuries later for their insightful descriptions and analyses. The first formal account of scurvy was by Jacques de Vitry in his "Historie des Croisades" in 1210:
"A large number of men in our army were attacked by a certain pestilence, against which the doctors could not find any remedy in their art. A sudden pain seized the feet and legs; immediately afterward the gums and teeth were attacked by a sort of gangrene, so the patient could not eat any more. Then the bones of the legs became horribly black, and so, after having suffered continued pain ... a large number of Christians went to rest on the bosom of the Lord."8
Three centuries later (in 1536) Jacques Cartier attempted the first treatment of a similar blight with tree bark and sap. The description appeared in Richard Hakluyt's The Principall Navigations (1600), appropriately entitled: "How by the grace of god we had notice of a certaine tree, whereby we all recovered our health: and the maner how to use it."9 The first randomized trial of the treatment of scurvy was reported in 1753 by James Lind.10 His classic description begins:
On the 20th of May 1747, I took 12 patients in the scurvy, on board the Salisbury at sea. Their cases were familiar as I could have them. They all in general had putrid gums, the spots of lassitude, with weakness of their knees ... and had one diet common to all, viz. water-gruel sweetened with sugar in the morning; fresh mutton-broth often times for dinner; at other times puddings, boiled biscuit with sugar, etc; and for supper, barley and raisins, rice and currants, sago and wine, or the like.
Two of these ... had each two oranges and one lemon given them every day.... They continued but 6 days under this course, having consumed the quantity that could be spared.
The consequence was, that the most sudden and visible good effects were perceived from the use of oranges and lemons; one of those who had taken them, being at the end of 6 days fit for duty.... The other was the best recovered of any in his condition; and being now deemed pretty well, as appointed nurse to the rest of the sick....
As I shall occasion elsewhere to take notice of the effects of other medicines in this disease, I shall here only observe, that the result of all my experiments was, that oranges and lemons were the most effectual remedies for this distemper at sea....
It may now be proper to confirm the efficacy of these fruits by the experience of others.
Notwithstanding this discovery and continuing investigations, the decline of scurvy among British sailors did not begin until citrus consumption was mandated by the Merchant Shipping Amendment Act of 1867.11
Data from the US Census in 1910 indicated the rarity of the disease even then with 68 (0.0084%) of 805412 reported deaths; this was a more common cause of death than plague, leprosy, glanders, anthrax, rabies, and chronic occupational poisonings other than lead and slightly less common than smallpox, pellagra, and chronic lead poisoning.12
Scurvy today is usually found among the elderly, the poor, alcoholics, and those restricted to macrobiotic diets or other diets that contain <10 mg/day of vitamin C. The US Department of Agriculture recommended daily allowance of vitamin C is 90 mg. Vitamin C is necessary as an antioxidant, for the synthesis of carnitine, collagen, and norepinephrine, and in prostaglandin metabolism. Manifestations of scurvy are largely related to underlying small hemorrhages, abnormal mitochondrial metabolism, and abnormal collagen synthesis and may manifest as bleeding gums and hemarthroses, arthralgias, malaise, and weakness.13
Autistic children typically restrict their diet and prefer foods of smooth texture (ie, pureed foods).14 Food-avoidant behaviors among these children can also be related to food presentation or specific utensil use. A review of the dietary patterns of 175 autistic children suggested that a taste "habituation" to sweet and salty foods was characteristic; high-glycemic-index foods were consistently preferred over others.15 Review of the literature reveals 23 case reports of scurvy in children with behaviorally restricted diets (see Table 2), including 2 children with autism16,17 and another with an unspecified behavioral problem,18 1 with trisomy 21,19 1 with static encephalopathy after pertussis-associated encephalitis,19 2 with cerebral palsy,20,21 4 with mental retardation,19,22–24 and 5 with global developmental delay6,19,25; 7 otherwise reportedly normal children, including 1 morbidly obese teenager26 and another with a pathologic grief reaction,27 had scurvy in association with unusual nonfaddist diets and isolated food-avoidant behaviors.28–32 Recurrent themes in most of these reports were prolonged diagnostic workups, inadequate initial dietary history, diets similar to those described above,15 and authors' impressions of the uniqueness of each presentation. Cases of childhood scurvy after infancy have been reported among the poor or those with parentally determined diets, including 6 obese children in a series of 28 children described in Thailand.33
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Vitamin C supplementation was followed by improvement in range of motion in his legs, behavior, and pain control. A gastrostomy tube was placed for adequate caloric and vitamin intake. Two months later, he had returned to school and gained 12 lb. Six months after his hospitalization he had a 20-lb weight gain, had made a friend in school, and, although his behavioral problems persisted, his language had improved to 2- to 3-word phrases.
Case2.
A 17-year-old boy presented with seizures and tetany. He is a resident of Washington Heights, New York City, of black and Dominican ancestry, with a history of sickle trait and mild asthma that required occasional albuterol inhalers. He is mildly mentally retarded and attended special school with "mainstreaming" for some classes. His cognitive and social function has been stable. His mother exhibits signs of mild mental retardation and had adult-onset Graves' disease.
The patient watched movies until 5 AM on the morning of admission. After 3 hours of sleep he awoke, and his mother was alerted by a cry from his room. She found him unresponsive with whole-body stiffening followed by limb-jerking and eye deviation. The convulsion ended after 2 minutes, but he remained confused for another 15 minutes. After awakening, he complained of cramping leg pain and was brought to the hospital.
Examination in the emergency department revealed leg tenderness with diminished motion. He was awake and normally interactive. He was hyporeflexic. Chvostek and Trousseau signs were present. The general examination was normal. Laboratory investigations showed a calcium level of 4.5 mg/dL (reference range: 8.7–10.0 mg/dL) and ionized calcium level of 0.61 mM/L (reference range: 1.12–1.32 mM/L); he had no evidence of renal insufficiency. A 2-minute seizure observed in the emergency department was aborted with intravenous lorazepam. He maintained a frog-leg position while sedated. He experienced several episodes of tetany of the trunk and arms. Both the seizures and tetany were abolished by parenteral calcium repletion. Subsequent laboratory values revealed an appropriately high parathyroid hormone level (515 pg/mL [reference range: 8–51 pg/mL]), a slightly high phosphorous level (5.0 mg/dL [reference range: 2.5–4.3 mg/dL]), and elevated creatine kinase level (1516 U/L [reference range: 51–294 U/L]). A skeletal survey revealed no dystrophic calcification, but there was marked osteopenia and bilateral femoral neck fractures, which were treated with open reduction and internal fixation. Both 1,25-OH and 25-OH vitamin D levels were undetectable. Laboratory values 7 years before presentation showed a normal serum calcium level.
The patient had no recent history of paresthesias, leg cramping, cognitive decline, psychosis, or muscle pains. Dietary reporting was inconsistent. His mother described a poor diet consisting largely of fast foods, including his favorite food: cheese pizza. The patient reported a diet of fried or prepared foods, supplemented with eggs, cheese, and daily chocolate milk. He drank 
3 L of carbonated cola daily. He had no identified sources of excessive fluoride ingestion. He reported taking 3 children's chewable vitamins nearly daily from 5 years of age. These vitamins contained 400 IU of vitamin D in each tablet. His mother did not corroborate his reported vitamin intake. He was active in sports including basketball and football throughout the year but remained indoors during the winter. Two days before admission he played in a local indoor basketball game for >1 hour without fatigue or cramping. He denied symptoms of malabsorption.
Subsequent investigations indicated depleted liver stores of fat-soluble vitamins. His serum 
-tocopherol level was 3.8 mg/L (reference range: 5.5–18.0 mg/L), 
-tocopherol level was 0.7 mg/L (reference range: 0.0–6.0 mg/L), retinol level was 0.07 mg/L (reference range: 0.26–0.70 mg/L), and retinyl palmitate level was 0.00 mg/L (reference range: 0.00–0.10 mg/L). Results of coagulation studies were normal (prothrombin time: 15.0 seconds [reference range: 12.7–15.4 seconds]; international normalized ratio: 1.12). The elevated phosphate level was unexpected in the setting of hyperparathyroidism and, if not a laboratory error, may have been attributable to rhabdomyolysis provoked by tetany and seizures. Subsequent phosphate values declined to within reference levels 2 hours later, after receiving initial parenteral calcium therapy; he became hypophosphatemic by hospital day 5. Without evidence for malabsorption, the subsequent normalization of serum fat-soluble vitamin levels after supplementation strongly suggested primary nutritional deficiency as the etiology of his acquired hypocalcemia. The subsequent clinical course was complicated by avascular necrosis of the femoral heads, which required removal of his orthopedic hardware 10 months after his original presentation.
Discussion
Vitamin D deficiency is associated with several common syndromes. Rickets, a childhood form of vitamin D deficiency, was first described in Daniel Whistler's 1644 thesis, De Morbo Puerile Anglorum Quem Patrio Idiomate Indignae Vocant the Rickets.40 It remains frequent in developing nations41 and is usually related to a combination of inadequate dietary intake and exposure to sunlight. Wharton and Bishop42 reviewed the epidemiology and pathophysiology of rickets including the inadequate mineralization of osteoid and other consequences of hypocalcemia, including seizures. Vitamin D deficiency in adults manifests as osteoporosis or osteopenia and is particularly prevalent in elderly patients with hip fracture.43
A growing body of evidence reflects high rates of acquired hypocalcemia and hypovitaminosis D in children and adolescents. Associated risk factors include maternal antenatal vitamin D intake and sun exposure,44 black and Hispanic ethnicity, winter and spring seasons, BMI, low milk and high fruit juice/soft-drink consumption, and infrequent physical activity.45 That this patient presented toward the end of winter in a northern American city (New York City lies at latitude 40°N) may be significant. Among 307 otherwise well 11- to 18-year-olds in urban Boston (latitude 42°N), 24.1% were vitamin D deficient.45 In a study of 9- to 16-year-old children who presented at the end of winter to a pediatric emergency facility in Edmonton, Alberta, Canada (latitude 52°N), 69% of the boys and 35% of the girls had vitamin D insufficiency (considered to be <40 nmol/L); no patients manifested vitamin D deficiency when intake exceeded 0.45 µg/kg per day.46 In Helsinki, Finland (latitude 60°N), 61.8% of 178 otherwise well 14- to 16-year-old girls were vitamin D deficient during winter, which was significantly associated with low bone mineral density.47 The American population is gradually drifting southward, yet 50% of Americans still live north of latitude 39°N.48 However, winter vitamin D deficiency was found in one third of black patients aged 12 to 29 years49 living in the South.
Long-bone fracture attributed to acquired vitamin D deficiency in otherwise normal pubertal and adolescent patients has not been described. This case demonstrates that careful dietary scrutiny and empiric vitamin supplementation may be necessary, even with reportedly sufficient dietary vitamin D.
CONCLUSIONS
These cases emphasize the role of comprehensive history-taking in the recognition of classic deficiency diseases. Idiosyncratic diets are common in the population, albeit more likely in patients with cognitive and communication disorders. An apparently normal diet should not preclude appropriate supplementation. Professional focus on the consequences of excess caloric intake should not lead physicians to neglect the potential for malnutrition, particularly among young and otherwise healthy children. A careful assessment of the diet and, when appropriate, screening for vitamin deficiencies should be an integral part of every child's medical care.
ACKNOWLEDGMENTS
OGT 918–007, a phase I/II controlled trial of n-butyldeoxynojirimycin in adult and juvenile Niemann-Pick disease, type C, was given clinical support by Actelion Pharmaceuticals, Inc (Dr Patterson, principal investigator).
We thank Jay Selman, MD, for assistance with case 1 and Deborah M. Levy, MD, for superb diagnostic acumen.
FOOTNOTES
Accepted Sep 22, 2006.
Address correspondence to James McCallum Noble, MD, Department of Neurology, Neurological Institute of New York, Columbia University Medical Center, 710 W 168th St, New York, NY 10032. E-mail: jn2054{at}columbia.edu
Financial Disclosure: Dr Patterson served on the advisory boards of and/or served as a consultant for Actelion Pharmaceuticals, Inc, Amicus Therapeutics, and Stem Cells, Inc (no honoraria were retained). The other authors have indicated they have no financial relationships relevant to this article to disclose.
REFERENCES
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