Index of Suspicion In the Nursery

Abstract

A 9-day-old Hispanic boy presents to the emergency department with seizures and apnea. The seizure lasts for about 3 minutes and is characterized by stiffening of the body and laryngospasm. Laboratory evaluation reveals a serum calcium concentration of 6 mg/dL (1.5 mmol/L). Hypocalcemic tetany resolves after administration of intravenous calcium. The infant also has fever of 100.4°F (37.7°C).The infant was born at term, and his birthweight was 3.2 kg. He is the fifth child born of nonconsanguineous parentage. The antenatal period was uneventful. Because the family does not have insurance, the mother had not taken prenatal vitamins and supplements. The baby has been fed with human milk and formula.On physical examination upon admission to the hospital, his temperature is 99°F (36.9°C), pulse is 186 beats/min, respiratory rate is 54 breaths/min, blood pressure is 97/64 mm Hg, and weight is 3.83 kg. He has no dysmorphic features and is normocephalic, with an open and flat anterior fontanelle without craniotabes. No cataracts or Chvostek sign are present. Cardiovascular examination reveals a regular heart rate and rhythm, with no murmurs. The lungs are clear to auscultation bilaterally, and there is no hepatosplenomegaly. Neurologic findings are normal.Laboratory evaluation reveals: sodium, 136 mEq/L (136 mmol/L); potassium, 5.2 mEq/L (5.2 mmol/L); chloride, 101 mEq/L (101 mmol/L); bicarbonate, 26 mEq/L (26 mmol/L); blood urea nitrogen, 10 mg/dL (3.57 mmol/L); creatinine, 0.3 mg/dL (26.5 mcmol/L); glucose, 109 mg/dL (6.1 mmol/L); calcium, 6.6 mg/dL (1.65 mmol/L); phosphorous, 10.5 mg/dL (3.4 mmol/L); albumin, 3.0 g/dL (30 g/L); and magnesium, 2 mg/dL (0.82 mmol/L). The white blood cell count and differential count are normal. Findings on cerebrospinal fluid evaluation are normal. However, the 25-hydroxyvitamin D concentration is less than 7 ng/mL (17.5 nmol/L) (normal, 10 to 68 ng/mL [25 to 169.7 nmol/L]), the 1,25-dihydroxyvitamin D concentration is 45 pg/mL (117 pmol/L) (normal), and the parathyroid hormone level is intact at 52 pg/mL (5.5 pmol/L) (normal, 10 to 65 pg/mL [1.5 to 6.8 pmol/L]). The ionized calcium concentration is 3.2 mg/dL (0.8 mmol/L) (low) at a pH of 7.39.Hypocalcemia is a well-recognized cause of neonatal seizures. The usual causes of hypocalcemia are hypoparathyroidism, vitamin D deficiency, and sepsis. The combination of low serum calcium, elevated serum phosphorous, and inappropriately normal parathyroid hormone (PTH) levels in the face of hypocalcemia confirms the diagnosis of hypoparathyroidism. Additionally, the patient had low 25-hydroxyvitamin D levels. Being born to a multigravida female who had not had any nutrient supplements placed him at risk for vitamin D deficiency. This suspicion was confirmed upon measurement of the mother’s 25- hydroxyvitamin D level.The infant was diagnosed with transient hypoparathyroidism concomitant with vitamin D deficiency. He did not have classic rachitic changes on radiographic evaluation. The hypoparathyroidism improved subsequently, as evidenced by an appropriate response of parathyroid hormone (ie, a decline in concentration) to the administration of calcium. (The elevated serum phosphorous concentration may not resolve acutely and cannot be used as an indirect measure of hypoparathyroidism.) Mother and baby were treated with ergocalciferol and calcium supplements.Calcium metabolism is regulated primarily by vitamin D and PTH. PTH promotes calcium absorption from the intestine, stimulates osteoblasts in the bone to promote calcium release, and converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D in the kidney. The hormone also causes phosphaturia. Hence, hyperphosphatemia and hypocalcemia are the hallmarks of hypoparathyroidism. Magnesium is essential for the release and function of PTH, and magnesium levels should be corrected when treating hypocalcemia. (2) Sepsis also can cause transient hypoparathyroidism. Most cases of neonatal hypoparathyroidism are transient because of the physiologic immaturity of the parathyroid gland. However, persistent and significant hypoparathyroidism requires extensive evaluation to rule out DiGeorge syndrome or velocardiofacial syndrome by determination with fluorescent in situ hybridization probe of microdeletions in chromosome 22q11-pter. (1) Other rarer conditions that include hypoparathyroidism are Kearns-Sayre and Kenny-Caffey syndromes, which are mitochondrial cytopathies.The vitamin D status of an infant depends on several factors: the amount of calcidiol (25-hydroxyvitamin D) transferred from the mother prenatally, dietary vitamin D consumption, and vitamin D production by the skin during exposure to ultraviolet light. Because the half-life of calcidiol is approximately 3 to 4 weeks, (2) the serum concentration of vitamin D declines rapidly ex utero unless the infant receives nutritional sources of the vitamin.Human milk typically contains less than 25 IU of vitamin D per liter (3) unless the mother receives high-dose vitamin D supplementation (eg, 2,000 IU/d). Because dark-skinned individuals (African-Americans and Asians) produce less vitamin D in response to ultraviolet sunlight, the vitamin D concentration of the milk of dark-skinned mothers is less than that of lighter-skinned mothers. (4)Traditionally, vitamin D deficiency is described in three progressive stages. The first represents impaired intestinal calcium absorption, resulting in hypocalcemia and compensatory elevation of PTH levels that subsequently normalize calcium concentrations. Hypophosphatemia develops in the second stage as an aftermath of the secondary hyperparathyroidism. The latter also promotes increased calcium mobilization from the skeleton, renal reabsorption of calcium, and the renal 1 alpha-hydroxylation of 25-hydroxyvitamin D. In the third stage, radiologic findings of rickets become apparent in conjunction with depressed serum calcium and phosphorous concentrations. The hyperaminoaciduria and hyperphosphaturia that occur in the later stages provide indirect evidence of florid secondary hyperparathyroidism. Serum PTH concentrations are elevated in all three stages. Therefore, measurement of serum phosphate and PTH is diagnostically useful in neonatal hypocalcemia for distinguishing vitamin D deficiency from hypoparathyroidism.In profound vitamin D deficiency, the level of 1,25-dihydroxyvitamin D usually is low, but in moderate, classic vitamin D deficiency, stimulation of renal proximal tubular 1 alpha-hydroxylase by PTH can result in a normal or even elevated levels of 1,25-dihydroxyvitamin D. The high levels of 1,25-dihydroxyvitamin D reflect the action of PTH on the renal 1 alpha-hydroxylase.Early neonatal hypocalcemia sometimes is encountered with maternal diabetes, birth asphyxia, sepsis (macrophage-generated cytokines can affect PTH secretion and action), and preterm birth. Increased levels of calcitonin, resistance to PTH action, decreased PTH secretion, and resistance to calcitriol all have been implicated as pathologic mechanisms in these disorders. (5)Infants of hyperparathyroid mothers who have hypercalcemia can develop hypocalcemia as a result of neonatal PTH suppression (maternal transplacental flux of elevated calcium). The high phosphorous content of commercial milk formulas can precipitate hypocalcemia in some infants. (6) Hypoparathyroidism, as explained previously, can be either transient or permanent, and permanent hypoparathyroidism can be isolated or a component of syndromes. Another entity is autosomal dominant familial hypercalciuric hypocalcemia, which is due to mutations in the calcium-sensing receptor. (7)(8) This is characterized by low PTH levels or inappropriately normal PTH levels in the presence of ambient hypocalcemia-hyperphosphatemia, hypocalcemia, and hypercalciuria (calcium/creatinine ratio, 0.2) from early in life. Because these patients are at high risk for renal stones, hypocalcemia in this presentation should not be treated unless the patient is symptomatic.Pseudohypoparathyroidism, which is a peripheral resistance to circulating PTH, mimics the clinical and biochemical profile of hypoparathyroidism. Another cause of hypocalcemia is vitamin D deficiency, which could be due to dietary vitamin deficiency, malabsorption, liver disorders, medications that decrease 25-hydroxyvitamin D levels (calcidiol), or decreased renal production of 1,25-dihydroxyvitamin D (calcitriol) due to hypoparathyroidism, renal failure, mutations of 1 alpha-hydroxylase, or resistance to vitamin D action. African-Americans and Asians are prone to low vitamin D concentrations because of decreased absorption through the skin. Because human milk has relatively low levels of vitamin D, breastfed children should receive supplemental vitamin D.Biochemically, vitamin D-dependent rickets type I is characterized by hypocalcemia and secondary hyperparathyroidism. The only feature that differentiates this disorder from dietary vitamin D deficiency is the presence of normal or elevated levels of 25-hydroxyvitamin D accompanied by low levels of 1,25-dihydroxyvitamin D.Acute hypocalcemia constitutes an emergency that requires prompt attention. If symptoms of neuromuscular irritability are present and carpopedal spasm is elicited on physical examination, treatment with intravenous calcium is indicated until the signs and symptoms of hypocalcemia subside. Initially, a 10% solution of calcium gluconate (0.5 to 1 mL/kg) infused over 10 to 15 minutes is sufficient to terminate the seizures. This should be followed by continuous infusion of calcium gluconate at 500 mg/kg per 24 hours for neonates and 200 mg/kg per 24 hours for infants. Once the patient is stable, oral supplements frequently suffice.In cases of vitamin D deficiency or hypoparathyroidism, the metabolite of vitamin D chosen depends on the underlying disorder. If renal 1 alpha-hydroxylation is impaired, such as in hypoparathyroidism (or PTH resistance) or the vitamin D-dependent rickets syndromes, metabolites that do not require this enzymatic modification should be administered (calcitriol). In the patient in this case, hypoparathyroidism was transient, and vitamin D deficiency was confirmed by low 25-hydroxyvitamin D levels.The most widely used treatment for vitamin D deficiency is ergocalciferol. (1) The dose is 2,000 to 10,000 IU (40 IU=1 mcg) daily until the serum alkaline phosphatase concentration normalizes. In this case, after the test results were obtained, the baby was treated with ergocalciferol 5,000 IU orally. Ergocalciferol has a long half-life and replenishes vitamin D adipose depots. After initiation of therapy, it is essential to monitor the calcium, phosphorus, and alkaline phosphatase levels. Once the alkaline phosphatase concentration is normal, pharmacologic doses of vitamin D may be discontinued, but the recommended daily allowance of 400 IU ergocalciferol is maintained.Calcium intake should be encouraged after initiation of vitamin D therapy to prevent worsening of the hypocalcemia. In the presence of hypoparathyroidism, a dietary calcium:phosphorous ratio (wt/wt) of 4:1 is preferred to enhance calcium absorption. Hence, each feeding should be supplemented with calcium to ensure this ratio. Doing so provides an ample excess of calcium that will reduce phosphate absorption. This method of supplementation is superior to providing a fixed amount of calcium as separate boluses.Because total calcium in serum includes both the free (biologically active) and protein-bound components, ionized calcium should be measured when the diagnosis of hypocalcemia is considered, particularly in the setting of acute illness, premature or ill infants, malnutrition, or hypoalbuminemia. (9)Transient hypoparathyroidism is a relatively common cause of neonatal hypocalcemia, but the picture may be compounded by vitamin D deficiency. A thorough laboratory analysis should include measurement of serum electrolytes, including calcium, phosphorus, and magnesium, as well as PTH and alkaline phosphatase. When considered in conjunction with a detailed history, the findings will assist the physician in making a correct diagnosis.Newborns born to vitamin D-deficient mothers can present with rickets at birth, although classic vitamin D-deficiency rickets presents more commonly between 3 months and 3 years of age. In this age range, inadequate dietary vitamin D intake and diminished ultraviolet sun exposure (especially during winter months and at northern latitudes), when compounded with high endogenous calcium requirements, places the infant at risk. The simple, yet inexpensive, supplementation of vitamin D to breastfed infants guards against nutritional rickets.