Morning Report: What Next for Febrile, Fussy Infant?

Morning Report
Clinical Practice Pearls

Infant With Persistent Fever and Fussiness

A 4-week-old boy with tactile fever for the past 24 hours and fussiness of 2 weeks’ duration is referred to the emergency department (ED). His parents report that he cries ceaselessly until he eventually falls asleep. His formula intake and urine and stool output have been normal. However, on further questioning, the mother is inconsistent in her explanation of how she mixes the formula.

HISTORY
The infant was born at 38 weeks’ gestation to a 25-year-old gravida 1, para 0 after a normal spontaneous vaginal delivery. Apgar scores were 9 at both 1 and 5 minutes. The pregnancy and prenatal history were normal. Birth weight was 3500 g, length was 48 cm, and head circumference was 35 cm (all at the 50th percentile). At 1 week of life, his weight was 3400 g;
examination findings were otherwise unremarkable.

PHYSICAL EXAMINATION
The infant is extremely fussy but consolable. His temperature is 38.8°C (102°F) and blood pressure is 55/30 mm Hg; other vital signs are normal. There are no focal signs of infection. A review of systems yields normal findings.

LABORATORY RESULTS
A chemistry panel, obtained because of the possibility of incorrect formula concentration, is normal with the exception of a total calcium level of 5 mg/dL.

Answer on Next Page

Morning Report
Infant With Persistent Fever and Fussiness

To determine the cause of hypocalcemia, it is necessary to recall the mechanism of calcium homeostasis in the body. A calcium sensor on the parathyroid gland senses changes in the levels of ionized calcium. Low levels of ionized calcium trigger the release of PTH from the chief cells of the parathyroid gland. PTH has multiple sites of action. It acts directly on the distal renal tubule to increase calcium reabsorption (and phosphorus secretion) and mobilizes calcium and phosphorus from bone. It also stimulates the enzymatic activity of a1-hydroxylase in the kidney, which increases conversion of 25-hydroxyvitamin D to 1,25 dihydroxyvitamin D. The latter promotes calcium and phosphorus absorption from the GI tract and reabsorption from the renal tubules.
Thus, measurement of ionized calcium is a vital next step in the management of hypocalcemia. However, levels of PTH, magnesium, and 1,25 dihydroxyvitamin D should also be obtained because once calcium therapy is administered, these levels may become altered.

Neonatal hypocalcemia. Neonatal hypocalcemia usually presents within 72 hours after birth and is often transient. Low calcium levels can be secondary to maternal factors (vitamin D deficiency, gestational diabetes, hyperparathyroidism) or neonatal factors (prematurity, low birth weight, intrauterine growth restriction, birth asphyxia). Neonatal factors theoretically cause hypocalcemia through blunting of PTH secretion and elevation of calcitonin levels; however, delayed maturation of vitamin D pathways is another mechanism. Transient neonatal hypocalcemia may also be caused by sepsis, respiratory distress syndrome, hypomagnesemia, hyperbilirubinemia, renal failure, and alkalosis.

Other, less common causes of hypocalcemia include ingestion of cow’s milk, Albright hereditary osteodystrophy, and neonatal vitamin D deficiency or pseudodeficiency.

Less Common Causes of Hypocalcemia

Ingestion of cow’s milk. Infants fed cow’s milk instead of formula may also present with hypocalcemia. High phosphate loads in certain milks, such as cow’s milk, can have 7 times the phosphate load of breast milk. Hyperphosphatemia causes calcium precipitation and hypercalciuria, which lead to hypocalcemia. In addition, the infant kidney is less effective at hydroxylation of 25-hydroxyvitamin D to 1,25 dihydroxyvitamin D, which results in less calcium resorption from bone.

Albright hereditary osteodystrophy. Hypocalcemia may also be secondary to Albright hereditary osteodystrophy, which is characterized by pseudohypoparathyroidism, or end-organ unresponsiveness to PTH in children with normal glandular secretion. Such children are usually obese and have round facies, short stature, short fourth metacarpals, developmental delay, and fibrous bony changes.

Neonatal vitamin D deficiency or pseudodeficiency. In an infant with chronically low calcium levels, vitamin D intake and metabolism must be assessed. Chronic hypocalcemia may be the result of vitamin D–deficient rickets, caused by reduced vitamin D intake or low UV light exposure, or vitamin D–dependent rickets (type I), in which 25-hydroxyvitamin D cannot be converted to 1,25 dihydroxyvitamin D. Type II vitamin D–dependent rickets is characterized by end-organ unresponsiveness to vitamin D. Patients with familial hypophosphatemic rickets, which is caused by a defect in proximal tubular reabsorption of phosphorus from the kidney, usually have normal calcium levels.

Concomitant hypoparathyroidism. Hypoparathyroidism in a hypocalcemic child may signal DiGeorge syndrome (absence or malformation of the parathyroid glands). This syndrome encompasses a constellation of symptoms, including cardiac anomalies (ventricular septal defect, right aortic arch, tetralogy of Fallot), abnormal facies (micrognathia, prominent nose, narrow palpebral fissures, cleft palate), thymic hypoplasia, and hypocalcemia.

Outcome in this case. The infant’s ionized calcium level was 2.3 mg/dL. PTH and 1,25 dihydroxyvitamin D levels were normal. Magnesium levels were also normal, as were his phosphorus levels on regular formula—which was less suggestive of vitamin D deficiency. He was given calcium gluconate 100 mg/kg IV in the ED and low doses of oral calcium (approximately 20 mg/kg/d) during his hospitalization. His calcium levels quickly normalized, his irritability resolved, and he defervesced. The finding of situs inversus totalis on a chest radiograph prompted fluorescence in situ hybridization testing for 22q11 deletion; results were negative. Results of an upper GI series were normal. Blood, urine, and cerebrospinal fluid cultures showed no growth of bacteria. At discharge, the parents were instructed to continue oral calcium therapy and to follow up with the infant’s pediatrician. The hypocalcemia was thought to be secondary to possible infection. ■

Online Exclusive on Next Page

ONLINE EXCLUSIVE . . .

Less Common Causes of Hypocalcemia

Ingestion of cow’s milk. Infants fed cow’s milk instead of formula may also present with hypocalcemia. High phosphate loads in certain milks, such as cow’s milk, can have 7 times the phosphate load of breast milk. Hyperphosphatemia causes calcium precipitation and hypercalciuria, which lead to hypocalcemia. In addition, the infant kidney is less effective at hydroxylation of 25-hydroxyvitamin D to 1,25 dihydroxyvitamin D, which results in less calcium resorption from bone.

Albright hereditary osteodystrophy. Hypocalcemia may also be secondary to Albright hereditary osteodystrophy, which is characterized by pseudohypoparathyroidism, or end-organ unresponsiveness to PTH in children with normal glandular secretion. Such children are usually obese and have round facies, short stature, short fourth metacarpals, developmental delay, and fibrous bony changes.

Neonatal vitamin D deficiency or pseudodeficiency. In an infant with chronically low calcium levels, vitamin D intake and metabolism must be assessed. Chronic hypocalcemia may be the result of vitamin D–deficient rickets, caused by reduced vitamin D intake or low UV light exposure, or vitamin D–dependent rickets (type I), in which 25-hydroxyvitamin D cannot be converted to 1,25 dihydroxyvitamin D. Type II vitamin D–dependent rickets is characterized by end-organ unresponsiveness to vitamin D. Patients with familial hypophosphatemic rickets, which is caused by a defect in proximal tubular reabsorption of phosphorus from the kidney, usually have normal calcium levels.