This case involves a 10-month-old boy who developed persistent vomiting, weight loss, and dangerously high calcium levels (hypercalcemia). After extensive testing, doctors determined the cause was a rare genetic condition called CYP24A1 deficiency, which prevents the body from properly processing vitamin D. The diagnosis was confirmed through specialized blood tests showing abnormal vitamin D metabolism, and treatment focused on strict dietary management to prevent further calcium buildup and kidney damage.
Understanding a Complex Case: A 10-Month-Old Boy with Vomiting and High Calcium Levels
Table of Contents
- Case Presentation: The Patient's Story
- Medical History and Examination Findings
- Laboratory Test Results
- Differential Diagnosis: What Could Cause This?
- Genetic Disorders and Hypercalcemia
- Reaching the Final Diagnosis
- Confirmatory Diagnostic Testing
- Understanding Vitamin D Metabolism
- Treatment and Management Approach
- Clinical Implications for Patients
- Limitations of This Case Study
- Recommendations for Families
- Source Information
Case Presentation: The Patient's Story
A previously healthy 10-month-old boy was admitted to the hospital because of vomiting, weight loss, and dangerously high calcium levels in his blood (hypercalcemia). His symptoms began two weeks before admission when he started having projectile vomiting episodes every few days, typically after eating solid foods.
Despite the vomiting, the child remained active and alert between episodes. Over the next 12 days, the vomiting became more frequent, occurring daily and happening after drinking liquids as well. Two days before admission, he was evaluated at a pediatric clinic where he was found to be significantly underweight at 7.36 kg (only at the 0.4th percentile for his age).
His parents reported that he had developed a strong aversion to food, would gag at the sight of food, and had started refusing to eat anything by mouth. They also noted he seemed excessively thirsty and would drink large amounts of liquid when offered, even sucking water from washcloths during bathing.
Medical History and Examination Findings
The patient was born at 38 weeks gestation due to maternal gestational hypertension. He had received routine newborn care and met all normal developmental milestones. His growth had been normal until his 9-month checkup, when doctors noted his weight had dropped to the 1.6th percentile from the 27.1st percentile at 6 months.
His medical history included gastroesophageal reflux disease (GERD) and eczema. He was taking omeprazole for GERD but no vitamins or supplements. Family history revealed several relevant conditions: his father had GERD and melanoma with cardiomyopathy requiring heart transplantation, his paternal grandmother had Lynch syndrome and hyperparathyroidism, and his maternal uncle had DiGeorge syndrome.
On examination at admission, the child had a temperature of 36.1°C, blood pressure of 102/78 mm Hg, pulse of 140 beats per minute, and respiratory rate of 40 breaths per minute. He appeared alert but thin, with dry skin showing excoriations. His abdomen was soft without distention or tenderness, and muscle tone was normal.
Laboratory Test Results
Initial blood tests revealed critically high calcium levels of 13.2 mg/dL (normal range: 8.5-10.5 mg/dL). Other significant laboratory findings included:
- White blood cell count: 17,030/μL (slightly elevated)
- Platelet count: 494,000/μL (elevated)
- Parathyroid hormone (PTH) level: 6 pg/mL (low, indicating appropriate suppression)
- 25-hydroxyvitamin D: 64 ng/mL (high-normal range)
- 1,25-dihydroxyvitamin D: 37 pg/mL (normal range)
- Phosphorus: 3.6 mg/dL (slightly low)
Imaging studies showed medullary nephrocalcinosis (calcium deposits in both kidneys) but normal bone radiographs and abdominal ultrasounds.
Differential Diagnosis: What Could Cause This?
The medical team considered multiple possible causes for the child's hypercalcemia with suppressed parathyroid hormone levels. The main categories included:
- Endocrinopathies: Thyroid disorders, adrenal insufficiency, or metabolic disorders
- PTH-related peptide disorders: Rare tumors that secrete PTH-like substances
- Genetic disorders: Several inherited conditions that affect calcium metabolism
- Vitamin D metabolism disorders: Problems with how the body processes vitamin D
The normal thyroid function tests, lack of evidence for tumors, and absence of physical findings suggestive of genetic syndromes like Williams syndrome helped narrow the possibilities. The appropriately suppressed PTH level with high-normal vitamin D levels pointed toward a disorder of vitamin D metabolism.
Genetic Disorders and Hypercalcemia
The doctors considered several genetic disorders that can cause hypercalcemia in infants:
- Hypophosphatasia: A rare disorder causing poor bone mineralization, but this patient had normal bone radiographs and slightly low phosphorus levels instead of the expected high phosphorus
- Jansen's metaphyseal chondrodysplasia: Causes abnormal bone development and hypercalcemia, but the patient had no radiographic evidence of metaphyseal changes
- Williams syndrome: A genetic deletion syndrome associated with hypercalcemia, cardiac problems, and developmental delays, but this patient had no characteristic features
- Idiopathic infantile hypercalcemia: A diagnosis of exclusion now known to often be caused by genetic variants affecting vitamin D metabolism
Reaching the Final Diagnosis
The combination of findings led to the suspicion of idiopathic infantile hypercalcemia caused by a genetic defect in vitamin D metabolism. Several key clues supported this diagnosis:
- Unexplained hypercalcemia with appropriately suppressed PTH
- High-normal 25-hydroxyvitamin D level (64 ng/mL) unusual for a New England infant without supplementation
- Normal 1,25-dihydroxyvitamin D level that was actually inappropriately high given the suppressed PTH
- Presence of nephrocalcinosis indicating long-standing calcium metabolism problems
- Normal development and absence of other physical abnormalities
The doctors suspected a mutation in the CYP24A1 gene, which provides instructions for making the 24-hydroxylase enzyme critical for breaking down vitamin D.
Confirmatory Diagnostic Testing
Specialized testing was performed to confirm the diagnosis. When repeated two weeks after admission, the 1,25-dihydroxyvitamin D level was elevated to 120 pg/mL. More importantly, testing revealed:
- 24,25-dihydroxyvitamin D level: 0.4 ng/mL (significantly below the normal reference range of 1.6±1)
- Ratio of 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D: 170 ng/ng (dramatically elevated compared to the normal range of 7-35)
This abnormal ratio indicated impaired vitamin D metabolism, consistent with biallelic (recessive) variants in the CYP24A1 gene. The extremely low level of 24,25-dihydroxyvitamin D demonstrated reduced activity of the 24-hydroxylase enzyme, which normally helps prevent vitamin D toxicity by breaking down active vitamin D metabolites.
Understanding Vitamin D Metabolism
Vitamin D metabolism is a complex process that involves multiple steps and enzymes:
- Vitamin D from sunlight or diet is converted to 25-hydroxyvitamin D by the liver
- The kidneys then convert this to active 1,25-dihydroxyvitamin D using the 1α-hydroxylase enzyme
- Both forms can be inactivated by the 24-hydroxylase enzyme (CYP24A1) into forms that can be excreted
When CYP24A1 doesn't function properly due to genetic mutations, vitamin D and its active metabolites accumulate, leading to excessive calcium absorption from the diet and resulting in hypercalcemia. This explains why patients with this condition must strictly limit both dietary vitamin D and calcium intake.
Treatment and Management Approach
Treatment for CYP24A1 deficiency focuses on reducing vitamin D exposure and calcium intake:
- Dietary restrictions: Limiting foods high in vitamin D and calcium
- Sunlight avoidance: Reducing UVB exposure to minimize endogenous vitamin D production
- Medications: In some cases, azole antifungal drugs (like ketoconazole) may be used to inhibit vitamin D activation, or drugs like rifampin that enhance vitamin D breakdown through alternative pathways
- Hydration: Ensuring adequate fluid intake to help flush excess calcium
Patients require lifelong management and monitoring of calcium and vitamin D levels to prevent complications like kidney stones and nephrocalcinosis.
Clinical Implications for Patients
This case illustrates several important points for patients and families dealing with unexplained hypercalcemia:
- Unexplained hypercalcemia in infants requires thorough investigation
- Genetic causes are more common than acquired causes in very young patients
- CYP24A1 deficiency, while rare, should be considered in cases of PTH-independent hypercalcemia with appropriate vitamin D levels
- Early diagnosis is crucial to prevent long-term kidney damage from nephrocalcinosis
- Family history may provide important clues, as this condition follows an autosomal recessive inheritance pattern
Patients with this condition can lead normal lives with proper dietary management and regular monitoring.
Limitations of This Case Study
While this case provides valuable insights, several limitations should be noted:
- This is a single case report, and findings may not apply to all patients with similar presentations
- The diagnosis was made based on biochemical testing rather than direct genetic sequencing in this initial report
- Long-term follow-up data are not provided, so the chronic management challenges aren't fully detailed
- The response to specific treatments beyond dietary management isn't described
- Family genetic testing results aren't included to confirm the inheritance pattern
Recommendations for Families
For families dealing with similar health concerns, this case suggests several important actions:
- Seek prompt medical attention for persistent vomiting and feeding problems in infants
- Ensure growth parameters (weight, height) are carefully tracked at well-child visits
- Share complete family medical history with healthcare providers, as genetic conditions often run in families
- Ask about specific testing for calcium and vitamin D metabolism if hypercalcemia is detected
- Request referral to pediatric endocrinologists or genetic specialists for complex metabolic disorders
- Follow dietary recommendations strictly if a vitamin D metabolism disorder is diagnosed
- Ensure regular monitoring of kidney function and calcium levels with long-term follow-up care
Source Information
Original Article Title: Case 21-2024: A 10-Month-Old Boy with Vomiting and Hypercalcemia
Authors: Christina Jacobsen, M.D., Ph.D., Harald Jüppner, M.D., and Deborah M. Mitchell, M.D.
Publication: The New England Journal of Medicine, July 11, 2024; 391:167-76
DOI: 10.1056/NEJMcpc2402485
This patient-friendly article is based on peer-reviewed research from the Case Records of the Massachusetts General Hospital.