What is the diagnosis for an adult patient with hypercalcemia of vitamin D, constantly low alkaline phosphatase (ALP) level, normal calcium level, and slightly elevated phosphorus level, not taking any vitamin D supplements?

Hypophosphatasia

Based on the clinical presentation of elevated 25-hydroxyvitamin D, persistently low alkaline phosphatase (ALP), normal calcium, and slightly elevated phosphorus without vitamin D supplementation, the most likely diagnosis is hypophosphatasia.

Diagnostic Reasoning

The constellation of findings points specifically to hypophosphatasia, a rare genetic disorder characterized by deficient activity of tissue-nonspecific alkaline phosphatase:

• Persistently low ALP is the pathognomonic feature that distinguishes this condition from other metabolic bone diseases 1
• Normal calcium with slightly elevated phosphorus is consistent with hypophosphatasia, particularly during non-hypercalcemic phases 1
• Elevated 25-hydroxyvitamin D without supplementation can occur in hypophosphatasia, as these patients may have altered vitamin D metabolism 1

Key Biochemical Pattern in Hypophosphatasia

The biochemical profile evolves through different stages:

• Initial hypercalcemic stage: Serum calcium may be elevated with normal 25-hydroxyvitamin D levels, low urinary cyclic AMP, and appropriately suppressed 1,25-dihydroxyvitamin D 1
• Normocalcemic stage: As described in your patient, with persistently low ALP being the constant feature 1
• The characteristic finding is that ALP remains well below normal range regardless of metabolic state, distinguishing it from rickets or osteomalacia where ALP is typically elevated 2, 3

Critical Distinguishing Features from Other Conditions

Why Not Vitamin D Intoxication?

• Vitamin D intoxication typically presents with normal or low ALP, not persistently low values 4
• VDI requires 25-hydroxyvitamin D levels above 150 ng/mL for diagnosis 4
• Patient is not taking supplements, making exogenous intoxication unlikely 4

Why Not X-Linked Hypophosphatemia (XLH)?

• XLH characteristically shows increased ALP levels, not decreased 2
• XLH presents with hypophosphatemia and low/normal calcium, but elevated ALP is a biochemical hallmark 2

Why Not Granulomatous Disease?

• Granulomatous diseases like sarcoidosis typically show elevated 1,25-dihydroxyvitamin D with low or normal 25-hydroxyvitamin D 5, 6
• ALP is usually normal or elevated in sarcoidosis, not characteristically low 5

Recommended Diagnostic Workup

To confirm hypophosphatasia, obtain:

• Plasma pyridoxal 5'-phosphate (PLP): Elevated levels are highly specific for hypophosphatasia due to ALP's role in PLP metabolism 1
• Urinary phosphoethanolamine: Elevated in hypophosphatasia 1
• Genetic testing: ALPL gene sequencing for definitive diagnosis 1
• Measure 1,25-dihydroxyvitamin D: In hypophosphatasia, this may be appropriately low during hypercalcemic phases or elevated during vitamin D deficiency phases 1
• Skeletal radiographs: Look for characteristic findings of rickets or osteomalacia despite low ALP 1

Clinical Implications and Monitoring

The persistently low ALP is the critical diagnostic clue that should prompt consideration of hypophosphatasia over other metabolic bone disorders:

• Unlike rickets/osteomalacia where ALP normalizes with healing, ALP returns to characteristically low levels in hypophosphatasia even after bone healing 1
• These patients may paradoxically develop vitamin D deficiency rickets if vitamin D intake is restricted, which causes ALP to rise markedly during active rickets, then return to low levels with healing 1
• Avoid excessive vitamin D supplementation as hypophosphatasia patients can develop hypercalcemia with modest vitamin D doses 7, 1

Common Pitfalls to Avoid

• Do not assume low ALP is a laboratory error: Persistently low ALP should trigger evaluation for hypophosphatasia 1
• Do not treat empirically with vitamin D: Hypophosphatasia patients may develop symptomatic hypercalcemia with standard vitamin D doses 7, 1
• Do not confuse with hypophosphatemic rickets: Most forms of hypophosphatemic rickets have elevated ALP, not decreased 2, 7