vitamin d and children | All AAP

An Unusual Cause Of Bone Pain In A 3-Year-Old Girl

Pediatrics In Review

March 1, 2025

A 3-year-old previously healthy female with history of a cow's milk allergy presents to the emergency department with a 2-week history of intermittent leg pain, chapped lips, and decreased oral intake. Her mother states that 2 weeks ago she noticed that her daughter had chapped lips and was eating less frequently. One week ago, she also developed an intermittent, pruritic rash on her arms that improved with cetirizine. She acutely became more tired 2 days prior to presentation and was refusing to walk or stand, prompting a visit to the emergency department for further evaluation.She does not take any medications other than a daily multivitamin. She follows a dairy-free diet and drinks up to 3 cups of rice milk per day. The patient has been afebrile. There is no known trauma or recent infections. Review of systems is negative for vision or hearing changes, shortness of breath, increased thirst, nausea, vomiting, diarrhea, or constipation. Other than expressive speech delay, developmental milestones are appropriate for age.Her vital signs are within normal limits. She weighs 11.9 kg (seventh percentile), with a body mass index of 13 kg/m2 (0.3 percentile). On physical exam she is tired but nontoxic appearing. She has dry mucous membranes and cheilitis. Her lower extremities are tender to palpation, and she is unwilling to bear weight. A pruritic, erythematous, blanching, maculopapular rash is present along the posterior trunk and several excoriation marks are noted on her upper arms, back, and abdomen. Heart, lung, and abdominal exams are unremarkable.Initial laboratory results (Table 1) reveal an elevated calcium at 13.1 mg/dL (8.8-10.8 mg/dL) with an ionized calcium of 1.68 mmol/L (1.12-1.32 mmol/L). Phosphate is 5.8 mg/dL (3.2-5.5 mg/dL). Erythrocyte sedimentation rate (ESR) is 30 mm/h (0-10 mm/h) and C-reactive protein is 0.3 mg/dL (<0.5 mg/dL). Complete blood count is normal. An electrocardiogram is obtained and is normal. Because of her level of hypercalcemia, a baseline renal ultrasound is obtained and demonstrates medullary nephrocalcinosis. Given the patient's elevated calcium level, she is admitted for further workup and management.The differential diagnosis for hypercalcemia is broad. Potential causes of hypercalcemia include mechanisms that lead to increased bone resorption, increased gastrointestinal absorption of calcium, and decreased renal excretion of calcium.1 A summary of a diagnostic pathway for hypercalcemia is provided in Figure 1.Parathyroid hormone (PTH), calcitriol (vitamin D:1,25 OH), and calcitonin are responsible for calcium homeostasis in the body. Once hypercalcemia is identified in a patient, the first step is to identify the level of PTH. A normal or increased PTH may point toward a differential diagnosis of familial hypocalciuric hypercalcemia or primary hyperparathyroidism respectively. The patient's PTH is low at 6.4 pg/mL (15.0-65.0 pg/mL) and urinary calcium/creatine ratio is 1337.0 mg/g (<400.0 mg/g), suggesting against both primary hyperparathyroidism and familial hypocalciuric hypercalcemia.In normal homeostasis, PTH secretion is sensitive to changes in serum calcium levels, with increased calcium levels inhibiting PTH release.2 Given that our patient's PTH levels were appropriately low, the next step is to determine the level of parathyroid related peptide (PTHrP). PTHrP can be ectopically secreted by malignant tumors and mimics biologic effects of PTH leading to paraneoplastic hypercalcemia.1,2 If PTHrP is normal or low however, the differential then includes vitamin D toxicity, vitamin A toxicity, granulomatous disease, hyperthyroidism, and pheochromocytoma.A PTHrP laboratory is performed. However, this laboratory test typically takes up to 5 days to determine a result, so in the meantime a broad workup is pursued. The elevated ESR noted on admission is thought to be secondary to an inflammatory state from hypercalcemia.3 Otherwise, in our patient, thyrotropin (TSH) is low at 0.25 uIU/mL (0.7-5.90 uIU/mL) and T4 is normal at 1.33 ng/dL (0.80-1.75 ng/dL), ruling out hyperthyroidism. Bilateral lower extremity imaging is obtained, which demonstrates dense metaphyseal bands seen in vitamin D toxicity, abnormalities in calcium-phosphate homeostasis, or malignancy (Figure 2).4 Vitamin D (25 OH) is normal at 46 ng/mL (25-80 ng/mL) and vitamin D (1,25 OH) is low at 10 pg/mL (20-70 pg/mL), ruling out vitamin D toxicity and granulomatous disease respectively. To screen for malignancy, a chest x-ray is obtained, which is normal. Lactate dehydrogenase and uric acid studies are normal. Urine catecholamines are within normal limits, suggesting against pheochromocytoma. Ultimately, PTHrP is low at 1.1 pmol/L (<4.2 pmol/L).The patient is found to have an elevated vitamin A level of 80 μg/dL (11.3-64.7 μg/dL). Additional nutrition history identified that the patient drinks 12 oz of rice milk per day (which contains 90 μg of vitamin A/ oz) and therefore averages up to 1080 μg of vitamin A daily. The recommended daily dose of vitamin A for her age is 300 μg.3,5,6 In addition, her grandmother also allows her to eat as many gummy vitamins as she desires and describes that she eats them 'like candy.' Further inquiry does not reveal that the patient has access to any other medications. She is diagnosed with vitamin A toxicity as the cause of her hypercalcemia.Vitamin A toxicity is a rare entity with few case reports represented in the literature.3,5 Vitamin A is a fat-soluble compound that is essential for growth, bone health, vision, and cell differentiation, and can only be acquired by diet.7 Vitamin A has a long biological half-life and accumulates in adipose tissue. Given that it is rapidly absorbed and slowly cleared, vitamin A toxicity can either be due to a large ingestion of vitamin A causing acute toxicity or chronic toxicity after prolonged intake of several doses.5,7 Signs and symptoms of vitamin A toxicity include headaches, nausea, vomiting, cheilitis, abdominal pain, rash, pruritus, bone pain, dysuria or polyuria, dizziness, and altered mental status.7 At toxic levels, vitamin A can also lead to bone resorption ultimately leading to hypercalcemia, though the mechanism is not well understood.5 Therefore, some symptoms present in vitamin A toxicity may also overlap with those present in patients with hypercalcemia. Additionally, excess vitamin A is associated with development of idiopathic intracranial hypertension, papilledema, and elevated triglycerides, which in turn may cause elevated liver enzymes as seen in this patient.7 Excess vitamin A is stored in stellate cells in the liver and accumulation can lead to their activation leading to liver injury.8The management of vitamin A toxicity starts with discontinuing further consumption of vitamin A. Given that vitamin A is stored in adipose tissue and is slowly cleared, close follow-up is needed to monitor the trend in levels.7Next, hypercalcemia secondary to vitamin A toxicity needs to be addressed. Treatment of hypercalcemia depends on the severity of the hypercalcemia as well as the symptoms the patient experiences.1,9,10 Hypercalcemia is classified as mild (Ca <12 mg/dL), moderate (Ca 12-14 mg/dL), or severe (Ca >14 mg/dL).1 Mild hypercalcemia does not necessarily require treatment if the patient is asymptomatic. Signs and symptoms of hypercalcemia include nephrocalcinosis, bone pain, nausea, vomiting, constipation, abdominal pain, neuropsychiatric manifestations (such as lethargy, confusion, or fatigue), muscle weakness, and cardiac arrhythmias.1,9The goals for treatment of hypercalcemia include stabilizing and reducing the calcium level with adequate hydration, increasing urinary calcium excretion, and inhibiting osteoclast activity in the bone.5 Therefore, the first step is to give intravenous hyperhydration, sometimes necessitating up to 2 times the maintenance fluid rate to achieve effect. If during treatment there is concern for fluid overload, diuretics such as furosemide may be needed to help with renal filtration of calcium. For some patients, hyperhydration is enough to correct hypercalcemia. Patients with symptomatic moderate hypercalcemia and severe hypercalcemia, regardless of symptoms, require more aggressive treatment and will need medications such as calcitonin or bisphosphonates to inhibit further osteoclastic resorption to correct the hypercalcemia.1,5,11 Calcitonin is approved for children to treat acute refractory hypercalcemia and was our choice because of its rapid onset of action; however, tachyphylaxis occurs quickly and persistent hypercalcemia will require bisphosphonate therapy. These are all temporizing measures and once the underlying etiology is resolved, the patient's calcium levels will also return to normal.Our patient's primary signs and symptoms from her hypercalcemia included bone pain, abdominal pain, decreased oral intake, and fatigue. Her initial calcium level was 13.1 mg/dL, placing her in the category of symptomatic moderate hypercalcemia. She was hyperhydrated with intravenous fluids running at 2 times her maintenance rate. Given her persistent hypercalcemia...

Journals & PublicationsHypercalcemiaBone PainThyrotropinParathyroid Hormone-Related Protein

https://publications.aap.org/pediatricsinreview/article/46/3/173/201117/An-Unusual-Cause-of-Bone-Pain-in-a-3-Year-Old-Girl

A Neonate With Anemia And Diarrhea

NeoReviews

October 1, 2024

A 26-day-old appropriate-for-gestational-age female infant born at term gestation to a 30-year-old gravida 4 mother (with 3 previous infant deaths) from a third-degree consanguineous relationship is referred to our NICU for increased frequency of stools. The mother has no significant medical or obstetrical illness. Antenatal scans are normal. The neonate is delivered vaginally at 39 weeks of gestation with a birthweight of 2,700 g, length of 49 cm, and head circumference of 33 cm (all the measurements are between the 10th and 90th percentile as per the modified Fenton chart). The infant is discharged on day 2 after birth and is exclusively breastfed.The neonate is healthy till the second week after birth and breastfeeding exclusively when parents notice 3 to 4 episodes of nonprojectile and nonbilious vomiting per day along with the passage of bulky, yellow, greasy, non-foul-smelling, and non-blood-tinged stools. These episodes are initially 2 per day and later increase to 6 to 8 per day. There is no history of seizures, lethargy, refusal to feed, involuntary movements, or abnormal odor from body secretions. There is a history of similar complaints in all the other siblings who died early in childhood, as depicted in the family tree (Fig 1). These siblings who died at 13 months, 2 months, and 5 months, respectively, had failure to thrive and global developmental delay with no attainment of milestones such as head holding or social smile.On examination, vital parameters are within normal limits with no signs of dehydration. There is inadequate weight gain of only 100 g since birth (4 g/day). Physical examination reveals pallor. There is no visible jaundice, edema, dysmorphism, cataract, hepatosplenomegaly, or hypoglycemia. The rest of the systemic examination, including the neurologic examination, is normal. The passage of greasy, bulky, and non-foul-smelling stools is confirmed after admission.Cystic fibrosisShwachman-Diamond syndromeInfections (Shigella, Salmonella, rotavirus, enterotoxigenic Escherichia coli)Inborn errors of metabolism: urea cycle defects, organic aciduriasAbetalipoproteinemia (ABL)Cow milk allergyImmunodeficiencyThe neonate underwent extensive evaluation to assess the cause of malabsorption and failure to thrive (Table 1).Given a triad of fat malabsorption causing failure to thrive, acanthocytosis, and hypocholesterolaemia, ABL was strongly suspected.Whole exome sequence revealed a homozygous splice site variant in intron 9 of the microsomal triglyceride transfer protein (MTTP) gene (chr4:g.99600734G>T), likely a pathogenic variant confirming the diagnosis of ABL.ABL, also known as Bassen-Kornzweig syndrome, is a rare autosomal recessive disorder characterized by mutations in the gene encoding the large subunit of the MTTP gene with an incidence of less than 1 in a million. (1)Deficiency of MTTP causes premature termination of the assembly of apolipoprotein (apo) B-containing lipoprotein in the intestine and liver, resulting in malabsorption of fat and fat-soluble vitamins.Known associations of ABL include failure to thrive, diarrhea, acanthocytosis, anemia, retinitis pigmentosa, ataxia, and myopathy including cardiomyopathy. Hematologic features of ABL include acanthocytosis (star-shaped cells comprising >50% erythrocytes), which is an early manifestation. Membrane deformation in acanthocytes occurs because of decreased membrane fluidity (increase in the sphingomyelin:lecithin ratio), making them vulnerable to splenic trapping and destruction, resulting in anemia. (2) Other factors contributing to anemia include iron and folate deficiency and, rarely, hemolysis because of tocopherol deficiency. Bleeding tendencies may occur because of vitamin K deficiency. Neuromuscular symptoms occur mainly because of vitamin E deficiency, ranging from diminished deep tendon reflexes to spinocerebellar ataxia, myopathy, peripheral neuropathy, muscular weakness, loss of vibration, and proprioception. Vitamin D deficiency may present with skeletal deformities and bone growth defects. (3) Ophthalmologic symptoms develop because of a deficiency of vitamins A and E secondary to malabsorption. Retinitis pigmentosa is typically present in adolescence. Alterations in visual acuity, loss of night vision, and color vision may precede, followed by a gradual loss of vision, as well as progressive scotoma, ultimately leading to complete loss of vision. (4) Vitamin A deficiency can also present as corneal ulcers and lacrimal gland dysfunction.Although no formal clinical criteria exist, absent or extremely low low-density lipoprotein cholesterol, triglycerides, and apoprotein B levels are diagnostic of ABL. Fecal fat studies may be helpful to narrow the differential if fat malabsorption is present. The intestinal endoscopic examination will show mucosal 'gelee blanche' (snowy appearance). (5) These tests were not done on our patient since she is a neonate.Molecular genetic testing is required to confirm MTTP gene mutations in the proband and decide the long-term prognosis as patients with the E4/E2 genotype had less favorable outcomes. (6) Parents also need to receive genetic counseling to know what the 25% recurrence (autosomal recessive inheritance) rate is and the options for prenatal diagnosis. The previous siblings of this index case died early in childhood and had global developmental delays but were not evaluated. This highlights the need for evaluating these cases and initiating early treatment to prevent neurodevelopmental impairment secondary to undernutrition and fat malabsorption.Treatment of ABL requires dietary modification including a low-fat diet with an intake of less than 30% or less than 5 g per day in children. (7) In case of inadequate weight gain, special low-fat infant feeding formulas and medium-chain triglyceride oil are recommended. Assessment of growth is a must in every visit. With proper treatment, infants may return to a normal growth velocity, although they may not reach their full growth potential. (8) Recommended daily supplementation includes vitamin E at 100 to 300 IU/kg, vitamin A at 100 to 400 IU/kg per day, vitamin D at 800 to 1,200 IU/day, vitamin K at 5 to 35 mg/week, and iron, folate, and vitamin B12 for anemia. (9)Neurodevelopment is guarded as many develop vision loss and permanent blindness and require long-term multidisciplinary follow-up. (8) If left untreated, these children develop debilitating complications that can reduce their life expectancy. (10) With lifelong high-dose oral fat-soluble vitamin treatment, longevity into the seventh and eighth decades of life, with relatively minimal symptoms, has been reported. Currently available evidence emphasizes the need to find novel treatment especially targeting the MTTP gene to completely cure this disease. (11)The neonate continued on exclusive breastfeeding with the addition of oral vitamin E at 100 IU/kg per day, gradually increasing to 400 IU/kg per day. Oral vitamin D wa...

Journals & PublicationsDiarrheaMicrosomal Triglyceride Transfer Protein

https://publications.aap.org/neoreviews/article/25/10/e648/199557/A-Neonate-with-Anemia-and-Diarrhea

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