What is the follow-up for a 2-year-old with developmental delay and hypercalcemia (elevated serum calcium level)?

Follow-Up of Elevated Serum Calcium (12 mg/dL) in a 2-Year-Old with Developmental Delay

Immediately initiate a comprehensive medical evaluation including objective vision and hearing testing, blood lead level, and metabolic workup while simultaneously referring to early intervention services—do not delay therapy while pursuing diagnostic investigations. 1

Immediate Diagnostic Workup

Essential Laboratory Tests

• Repeat serum calcium to confirm hypercalcemia (normal range for age: 8.8-10.8 mg/dL) 2
• Parathyroid hormone (PTH) level to differentiate PTH-mediated from non-PTH-mediated causes 2, 3
• Serum phosphate level (helps distinguish between different etiologies) 2
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels 2, 4
• Urinary calcium-to-creatinine ratio to assess for hypercalciuria and rule out familial hypocalciuric hypercalcemia 2, 4
• Blood lead level as part of standard developmental delay evaluation 1
• Complete blood count to screen for malignancy (acute lymphoblastic leukemia can present with hypercalcemia) 3

Additional Metabolic and Endocrine Testing

• PTH-related peptide (PTHrP) if PTH is suppressed 2
• Thyroid function tests (TSH, free T4) as hypothyroidism can contribute to developmental delay 5
• Renal function tests (creatinine, BUN) 2
• Alkaline phosphatase and bone-specific alkaline phosphatase 1

Imaging Studies

Required Imaging

• Renal ultrasonography to evaluate for nephrocalcinosis, which can occur with chronic hypercalcemia and hypercalciuria 2, 4
• Skeletal survey if malignancy is suspected (osteolytic lesions can be the presenting feature of ALL) 3
• Chest X-ray if granulomatous disease is considered 2

Neuroimaging Considerations

• Brain MRI should be obtained when specific clinical indicators are present in the context of developmental delay, particularly if dysmorphic features, microcephaly, macrocephaly, or neurological abnormalities are noted 6

Developmental Evaluation Components

Mandatory Assessments

• Objective vision evaluation (not just office screening) as visual impairment can contribute to developmental delay 1
• Formal audiologic testing (not just office screening) to rule out hearing impairment, which must be excluded first in children with developmental delays 7
• Standardized developmental assessment using tools such as Bayley Scales of Infant and Toddler Development or Battelle Developmental Inventory 1

Genetic Evaluation

• Chromosomal microarray (CMA) as first-line genetic testing, particularly given the association of hypercalcemia with chromosomal abnormalities such as 2p duplication syndrome 6, 2
• Whole exome sequencing if CMA is unrevealing and clinical suspicion for genetic syndrome remains high 6, 2
• Consider testing for SLC34A1 mutations (sodium-phosphate cotransporter defects) and CYP24A1 mutations (24-hydroxylase deficiency) in cases of hypercalcemia with hypercalciuria 4

Immediate Referrals (Do Not Delay)

Critical Referrals

• Early intervention services (Child Find/Early Intervention programs) should be initiated immediately without waiting for diagnostic clarification 1, 8
• Physical therapy focusing on gross motor development 8
• Occupational therapy for fine motor skills and sensory integration 8
• Speech and language evaluation including oral-motor functioning assessment 8

Subspecialist Referrals

• Pediatric endocrinology for management of hypercalcemia 2, 3
• Developmental pediatrician or pediatric neurologist for comprehensive evaluation of developmental delay 1, 6
• Clinical genetics if dysmorphic features are present or if chromosomal abnormality is suspected 1, 2

Management of Hypercalcemia

Acute Management (if symptomatic or calcium >13 mg/dL)

• Intravenous hydration with normal saline 2, 4
• Furosemide after adequate hydration 4
• Corticosteroids if vitamin D-mediated hypercalcemia is suspected 4
• Zoledronic acid in severe cases or malignancy-associated hypercalcemia 3

Dietary Modifications

• Restriction of calcium and vitamin D intake while etiology is being determined 4

Follow-Up Schedule

Short-Term Follow-Up

• Return visit within 1-2 weeks to review laboratory results and ensure referrals have been activated 1, 9
• Repeat calcium level within 1 week if initial level was >12 mg/dL 2
• Monitor for symptoms of hypercalcemia including vomiting, constipation, polyuria, and failure to thrive 2, 4

Ongoing Monitoring

• Monthly to quarterly visits for children under 5 years with developmental delay 1
• Serial growth measurements using CDC or WHO growth curves to monitor for failure to thrive 8
• Developmental surveillance at each visit with repeat standardized screening every 6 months until age 2, then yearly until age 5 6
• Renal ultrasonography every 1-2 years if hypercalciuria persists 1, 4

Critical Red Flags Requiring Urgent Action

• Loss of previously acquired developmental milestones (suggests neurodegenerative process) 8
• Severe hypercalcemia (>14 mg/dL) with symptoms 2, 3
• Abnormal complete blood count suggesting malignancy 3
• Respiratory difficulties or swallowing problems in the context of hypotonia 1, 8

Common Pitfalls to Avoid

• Do not delay early intervention services while waiting for a definitive diagnosis of either the hypercalcemia or developmental delay—therapy should begin immediately 1, 8
• Do not assume hypercalcemia is benign in a child with developmental delay; it may be the presenting feature of serious conditions including malignancy, genetic syndromes, or metabolic disorders 2, 3
• Do not rely on office-based hearing/vision screening alone—formal audiologic and ophthalmologic evaluations are mandatory 1, 7
• Do not overlook treatable causes of developmental delay such as hypothyroidism, lead toxicity, or specific genetic conditions 1, 5, 8