Hypotonia and Failure to Thrive in an 8-month-old Infant.

An 8-month-old unimmunized boy presents to the emergency department with 10 days of progressive weakness. He has become limp and too weak to roll over or hold his bottle, and he is disinterested in feeding and has lost weight. His parents have been administering him sips of a reconstituted sports drink. On review of systems, he has no rashes, vomiting, dyspnea, or seizures. He had common cold–like symptoms 2 weeks earlier that spontaneously resolved. His medical history reveals a normal perinatal course. At age 1 month he was transitioned from breastfeeding to a homemade preparation of cow milk fortified with cod-liver oil, butter oil, molasses, beef gelatin, honey, and vitamin D. Parents report use of enemas to relieve the constipation that he has had for several months. He has had no primary care visits. His family history reveals that his mother has neurofibromatosis type 1, and 4 cousins of his father died in infancy from Amish nemaline myopathy. On evaluation of milestones, at 2 months he had head control, at 6 months he sat with support and rolled back to front, but he has made no progress since. He is not sitting independently, crawling, or standing with support. He makes cooing sounds but is not yet babbling.He appears fussy and listless, with no dysmorphic features. He is febrile (temperature, 102.4°F [39.1°C]), with a heart rate of 153 beats/min, a respiratory rate of 44 breaths/min, an oxygen saturation of 100%, and blood pressure of 98/58 mm Hg. His weight is 15.6 lb (7.08 kg) (10th percentile), length is 68 cm (9th percentile), and head circumference is 42 cm (2nd percentile). He is normocephalic, has a sunken anterior fontanel, is not making tears, and has dry oral mucosa. His heart has regular rhythm with a grade 2/6 ejection systolic murmur. His capillary refill is 3 seconds, and skin turgor is decreased. His lungs are clear, abdomen is soft with no organomegaly, and external male genitalia are normal. On neuromuscular examination he lies frog-legged when supine, exhibits marked hypotonia on vertical and horizontal suspension, when seated is unable to prop himself or stay upright, shows decreased passive resistance at large joints, and makes no effort reaching forward. He exhibits normal grasp, normal deep tendon reflexes, no fasciculations, and no cranial nerve or focal deficits. Initial laboratory data reveal the following values: serum glucose, 68 mg/dL (3.77 mmol/L); sodium, 150 mEq/L (150 mmol/L); potassium, 3.2 mEq/L (3.2 mmol/L); bicarbonate, 24 mEq/L (24 mmol/L); blood urea nitrogen, 19 mg/dL (6.78 mmol/L); creatinine, 0.3 mg/dL (26.52 µmol/L); calcium, 18.4 mg/dL (4.60 mmol/L); magnesium, 1.6 mg/dL (0.66 mmol/L); phosphorus, 3.1 mg/dL (1.0 mmol/L); alkaline phosphatase, 111 U/L (1.85 µkat/L); serum osmolarity, 302 mOsm/kg (302 mmol/kg); and urinalysis with trace ketones and specific gravity less than 1.010. The respiratory pathogen panel is positive for enterovirus. His electrocardiogram has a shortened QTc of 350 milliseconds. He has normal findings on complete blood cell count, chest radiography, serum lactate level, and creatinine kinase level. Further evaluation reveals the diagnosis explaining his findings.Hypercalcemia is categorized as mild, moderate, or severe for serum calcium levels less than 12 mg/dL (<3.0 mmol/L), 12 to 14 mg/dL (3.0–3.5 mmol/L), and greater than 14 mg/dL (>3.5 mmol/L), respectively, and occurs extremely infrequently in children. (1) In an infant, hypotonia has an extensive differential diagnosis, and when presenting with dehydration, failure to thrive, and severe hypercalcemia, represents a medical emergency. A meticulous history and physical examination narrows the differential diagnosis from genetic, neurologic, neuromuscular, endocrinologic, nutritional, metabolic, infectious, and toxicological conditions causing acute weakness. Our patient’s history of being unimmunized, enteroviral infection, dietary supplementation, and family history warranted considering vaccine-preventable diseases, Guillain-Barre syndrome, infant botulism, and genetic disorders among causes for dehydration and weakness. However, these were inconsistent with his examination and laboratory data, particularly severe hypercalcemia.Figure 1 outlines an algorithm to evaluate a child with hypercalcemia. (2) Measuring parathyroid hormone (PTH) levels distinguishes PTH-mediated and PTH-independent mechanisms as primary hyperparathyroidism (PHPT), and malignancies account for more than 90% of hypercalcemia in the general population. In adults, PHPT results predominantly from parathyroid adenoma with unsuppressed PTH, contrary to hypercalcemia of malignancy. (3) Along with clinical features, serum levels of phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, alkaline phosphatase, and urinary calcium excretion help identify the etiology of hypercalcemia. Hypercalcemia in children occurs more commonly from PTH-independent conditions, including hypervitaminosis D (25-hydroxyvitamin D or 1,25-dihydroxyvitamin D), or from conditions affecting calcium excretion, such as drugs or mutations in calcium-sensing receptor. PHPT is extremely uncommon in children and presents in rare hereditary syndromes (Fig 1). Acquired conditions such as maternal hypocalcemia or tertiary hyperparathyroidism (during treatment of X-linked hypophosphatemia) remain rare causes of PTH-dependent hypercalcemia. (4)On further probing into his homemade formula, we calculated a vitamin D intake greater than 3,000 IU/d over 7 months from proportions of cod-liver oil, butter oil, and supplemental vitamin D. Further evaluation for hypercalcemia (Table 1) confirmed hypercalciuria, (5) PTH suppression, and elevated 25-hydroxyvitamin D with normal 1,25-dihydroxyvitamin D levels consistent with exogenous hypervitaminosis D.Vitamin D toxicity (VDT; also, vitamin D intoxication or hypervitaminosis D) is extremely rare, commonly manifesting as incidentally discovered hypercalcemia. (2)(7) Vitamin D is a popular supplement available over-the-counter, and if excessive doses are ingested, patients can develop toxicity. Symptoms are typically nonspecific: neuropsychiatric (cognitive and behavioral changes), neurologic (seizures, hypotonia), gastrointestinal (anorexia, vomiting, constipation), cardiovascular (arrhythmias), and renal (polyuria, renal colic). In infants, failure to thrive and dehydration may be the chief presentation. Investigations may reveal hyposomolar urine (<300 mmol/kg) with serum osmolarity greater than 295 mmol/L secondary to nephrogenic diabetes insipidus, hypercalciuria with shortened QTc, and flattened T waves on an electrocardiogram. (8)(9)Figure 2 outlines the steps in vitamin D metabolism. The prohormones vitamin D2 and vitamin D3, after hepatic conversion to 25-hydroxyvitamin D, are converted in the kidneys to the active metabolite 1,25-dihydroxyvitamin D, which regulates calcium and phosphorus homeostasis of renal, parathyroid, gastrointestinal, and skeletal physiology. Calcium-sensing receptor expressed in the parathyroid and kidney responds to serum calcium and regulates PTH release. (9) Typically, 25-hydroxyvitamin D levels need to exceed 80 ng/mL (>199.68 nmol/L) to cause hypercalcemia, with much higher levels causing symptomatic hypercalcemia. (10)(11)(12) Hypercalcemia leads to polyuria and induces nephrogenic diabetes insipidus by unclear mechanisms. (10)(12)The recommended age-based daily upper limits of vitamin D intake are 1,000 IU (0–6 months), 1,500 IU (6–12 months), 2,500 IU (1–5 years), 3,000 IU (4–8 years), and 4,000 IU (adolescents). (13) VDT from exogenous 25-hydroxyvitamin D is characterized by 25-hydroxyvitamin D levels greater than 150 ng/mL (>374.40 nmol/L), hypercalcemia, hypercalciuria, and suppressed PTH. Excess 25-hydroxyvitamin D displaces 1,25-dihydroxyvitamin D from vitamin D binding protein, and 1,25-dihydroxyvitamin D levels may be normal or only slightly increased but rarely reduced secondary to PTH suppression. VDT is rare even with stoss therapy—high-dose vitamin D therapy for nutritional rickets, or vitamin D deficiency in malabsorption. (14) Excessive sunlight exposure does not cause VDT because UV-B radiation stimulates both production and destruction of vitamin D3, maintaining equilibrium. (12)Hypercalcemia in VDT from administration of 1α-hydroxylated vitamin D analogues (calcitriol, alfacalcidol, paricalcitol) used in X-linked hypophosphatemic rickets and secondary hyperparathyroidism in end-stage renal disease is characterized by elevated 1,25-dihydroxyvitamin D levels. (11)Endogenous VDT arises from 1,25-dihydroxyvitamin D overproduction. In Williams-Beuren syndrome (also known as Williams syndrome), unclear aberrations in vitamin D metabolism effectively cause a state of hypervitaminosis D, leading to increased intestinal calcium absorption. (15) Individuals have elfin facies, learning disabilities, failure to thrive, supravalvular aortic stenosis, and nephrocalcinosis. Hypercalcemia, reported in up to 43% of cases, is usually mild, resolving by 2 years of age and accompanied by normal or elevated 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels, suggesting a PTH-independent mechanism with hypersensitivity to vitamin D. (15)(16)Extrarenal synthesis of 1,25-dihydroxyvitamin D from malignancies and granulomatous conditions (sarcoidosis, tuberculosis) is a cause of hypercalcemia in adults. Subcutaneous fat necrosis, a rare panniculitis after perinatal asphyxia, trauma, or hypothermia in term or postterm neonates, may present with life-threatening hypercalcemia due to 1,25-dihydroxyvitamin D secreted from activated macrophages. (2)(17)Loss-of-function mutations in the CYP24A1 gene (involved in vitamin D catabolism) or the SLC34A1 gene (coding for the Na+-dependent Pi cotransporter type IIa) are associated with infantile idiopathic hypercalcemia. Impaired inactivation of vitamin D metabolites in CYP24A1 gene mutation carriers leads to calcium absorption. In SLC34A1-mutated carriers, hypophosphatemia, and suppression of fibroblast growth factor 23 stimulates CYP27B1 with simultaneous inhibition of CYP24A1 (Fig 2). These manifest in early childhood with hypercalcemia, hypercalciuria, and nephrocalcinosis occasionally persisting undiagnosed into adulthood. These patients have PTH suppression, normal 25-hydroxyvitamin D concentrations, and upper-normal or slightly elevated serum 1,25-dihydroxyvitamin D levels, biochemically indistinguishable from 1,25-dihydroxyvitamin D elevation in granulomatous diseases. Patients with CYP24A1 mutations have low levels of 24,25-hydroxyvitamin D. A 25-hydroxyvitamin D/24,25-hydroxyvitamin D ratio greater than 80 indirectly estimates CYP24A1 activity. (11) These patients have hypersensitivity to vitamin D and are susceptible to hypercalcemia or nephrocalcinosis. (18)The treatment of VDT begins by removing the source of vitamin D and instituting dietary vitamin D and calcium restrictions. Vitamin D is stored in adipose tissue, and levels of 25-hydroxyvitamin D remain elevated for an extended period due to its half-life of 2 to 3 weeks, warranting serial monitoring. (10)(12) Immediate treatment of hypercalcemia is hyperhydration (1.5–2.0 times maintenance fluids) with 0.9% saline, facilitating calciuresis. After hydration is restored, adding a loop diuretic (furosemide, 1–2 mg/kg per day) can augment calciuresis. Prolonged diuresis is discouraged due to the risk of nephrocalcinosis. (9) Thiazides promote calcium reabsorption in the distal tubule and are avoided. Glucocorticoids and calcitonin are added if hypercalcemia persists. Prednisone has an onset of action in 24 to 72 hours. It inhibits renal calcium reabsorption and reduces intestinal calcium absorption by inhibiting 1,25-dihydroxyvitamin D activity. Glucocorticoids may be combined with calcitonin (2–4 IU/kg), which has a rapid, transient effect limited in duration due to tachyphylaxis. Bisphosphonates (pamidronate, alendronate) inhibit osteoclast-mediated bone resorption and are used to treat malignancy-associated hypercalcemia. Hemodialysis is a last recourse for unresponsive hypercalcemia and patients with renal failure. (2)(9)We started hyperhydration with normal saline and after restoration of volume status added furosemide for persistent hypercalcemia. His flow-murmur and fever resolved with rehydration. In consultation with metabolic specialists, we initiated a low-calcium, vitamin D–free formula. After 1 week, his calcium levels normalized (Fig 3A), with dramatic improvement in activity, feeding, and muscle tone. His vitamin D levels steadily declined after 3 months (Fig 3A), and he transitioned gradually to a normal diet. His growth parameters improved (Fig 3B), and motor development normalized by 14 months of age. His chromosomal microarray was normal, and targeted testing was negative for the CYP24A1c.428_430delAAG (p.Glu143del) variant of infantile idiopathic hypercalcemia found in the local Amish community (minor allele frequency, 3.3%; carrier frequency, 6.4%: Clinic for Special Children, unpublished data). (18)Ready availability of vitamin D and perceptions about its safety may result in inadvertent overdosing.A careful assessment of diet and supplements at health supervision visits can identify or prevent nutritional disorders.Clinicians must maintain a high index of suspicion to obtain serum calcium levels because symptoms of hypercalcemia are often nonspecific, are insidious, and can become life-threatening.Although exogenous hypervitaminosis D is more common, hypersensitivity to vitamin D from CYP24A1 and SLC34A1 mutations or Williams syndrome should be considered.Vitamin D toxicity resolves over weeks due to the slow release of vitamin D from adipose tissue and the prolonged half-life of 25-hydroxyvitamin D.