Inborn Errors of Metabolism Causing Neonatal Hypocalcemia and Failure to Thrive
Yes, several inborn errors of metabolism can present with neonatal hypocalcemia and failure to thrive, though they are relatively uncommon causes compared to more typical etiologies like prematurity or maternal diabetes. The most relevant metabolic disorders to consider include hypophosphatasia, certain organic acidemias, and disorders affecting vitamin D metabolism 1, 2.
Primary Metabolic Disorders to Consider
Hypophosphatasia
- This inborn error of metabolism presents with hypocalcemia and failure to thrive in the neonatal period 3
- It is characterized by low serum alkaline phosphatase levels, which distinguishes it from other causes of neonatal hypocalcemia 3
- Patients may exhibit skeletal abnormalities and poor bone mineralization 3
Organic Acidemias
- Classic organic acidemias (isovaleric acidemia, methylmalonic acidemia, propionic acidemia) can present with failure to thrive and metabolic disturbances in the neonatal period 1
- These disorders typically present with hyperammonemia, hypoglycemia, and/or ketolactic acidosis rather than isolated hypocalcemia 1
- Urine organic acid analysis is the key diagnostic test when these conditions are suspected 1
Disorders of Vitamin D Metabolism
- Inborn errors affecting vitamin D metabolism can cause hypocalcemia and failure to thrive 3, 2
- These include defects in 1-alpha-hydroxylase activity and vitamin D receptor abnormalities 3
Diagnostic Approach
Initial Laboratory Evaluation
- Obtain comprehensive metabolic panel including serum calcium (total and ionized), phosphate, magnesium, and alkaline phosphatase to characterize the hypocalcemia 4, 5
- Measure intact parathyroid hormone (PTH) to differentiate high PTH from low PTH causes 3
- Check vitamin D metabolites (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) 3, 5
- Perform urinalysis to assess for renal tubular disorders and measure urinary calcium, phosphate, and creatinine 4, 3
Specialized Metabolic Testing
- Urine organic acid analysis should be performed when metabolic encephalopathy, unexplained acidosis, or unusual odor accompanies hypocalcemia and failure to thrive 1, 2
- Plasma amino acids and acylcarnitine profile may identify amino acid disorders or fatty acid oxidation defects 2
- Serum ammonia should be checked if lethargy, poor feeding, or vomiting are prominent features 1, 2
Clinical Context Matters
- The timing of hypocalcemia presentation helps narrow the differential: early-onset (first 72 hours) versus late-onset hypocalcemia have different etiologies 5, 6
- Inborn errors of metabolism typically present with late-onset hypocalcemia after the first week of life, though exceptions exist 5, 6
- Associated features such as seizures, hypotonia, lethargy, metabolic acidosis, or hepatomegaly suggest specific metabolic disorders 1, 2
Important Caveats
More Common Causes Should Be Excluded First
- Prematurity, birth asphyxia, and maternal diabetes are far more common causes of neonatal hypocalcemia than inborn errors of metabolism 5, 6
- Excessive phosphate intake (from cow's milk formulas), hypomagnesemia, and vitamin D deficiency are the most common causes of late-onset hypocalcemia 5, 6
- Maternal calcium disorders (hypoparathyroidism or familial hypocalciuric hypercalcemia) can cause neonatal hypocalcemia and should be investigated 7
When to Suspect Metabolic Disease
- Consider inborn errors of metabolism when hypocalcemia occurs in a full-term infant without typical risk factors 2
- Persistent or recurrent hypocalcemia despite appropriate calcium supplementation warrants metabolic evaluation 5
- The presence of metabolic acidosis, hyperammonemia, or hypoglycemia alongside hypocalcemia increases suspicion for metabolic disorders 1, 2
- Failure to thrive that persists despite adequate nutritional support and correction of hypocalcemia suggests an underlying metabolic etiology 4, 2