What is the most likely diagnosis and recommended management for a patient with elevated intact parathyroid hormone (PTH), normal serum calcium, normal 25‑hydroxyvitamin D (25‑OH vitamin D), and low 24‑hour urinary calcium?

Familial Hypocalciuric Hypercalcemia (FHH) is the Most Likely Diagnosis

The combination of elevated PTH, normal serum calcium, normal vitamin D, and low 24‑hour urinary calcium (<100 mg/24h) is pathognomonic for familial hypocalciuric hypercalcemia (FHH) until proven otherwise. 1

Diagnostic Algorithm

Step 1: Calculate Calcium‑to‑Creatinine Clearance Ratio (CCCR)

• Measure a spot urine calcium‑to‑creatinine ratio or calculate CCCR from 24‑hour urine collections. 2
• A CCCR <0.01 strongly suggests FHH and distinguishes it from primary hyperparathyroidism, where CCCR is typically ≥0.01. 2
• In your case, the low 24‑hour urinary calcium already points toward FHH, but calculating CCCR provides definitive biochemical confirmation. 2

Step 2: Exclude Secondary Causes of Elevated PTH

Even though FHH is the leading diagnosis, you must systematically rule out secondary hyperparathyroidism:

• Confirm that 25‑hydroxyvitamin D is truly adequate (≥20 ng/mL, ideally ≥30 ng/mL). 1, 3 Vitamin D deficiency is the most common cause of elevated PTH with normal calcium. 1
• Verify dietary calcium intake meets age‑related recommendations (≈1,000–1,200 mg/day for adults). 1, 3 Low calcium intake can mimic secondary hyperparathyroidism by stimulating PTH secretion and reducing urinary calcium. 1
• Assess renal function (serum creatinine, eGFR). 1 PTH rises when eGFR falls below 60 mL/min/1.73 m², making chronic kidney disease a key differential. 1
• Check serum phosphorus. 1 Low‑normal or low phosphorus supports primary hyperparathyroidism or FHH (PTH enhances renal phosphate excretion), whereas normal or elevated phosphorus suggests secondary hyperparathyroidism from CKD or vitamin D deficiency. 1

Step 3: Confirm FHH with Genetic Testing

• If CCCR is <0.01 and secondary causes are excluded, proceed with genetic testing for CASR, GNA11, and AP2S1 mutations to confirm FHH. 2
• FHH is an autosomal dominant disorder; obtain a family history of hypercalcemia or failed parathyroidectomy. 2
• One study found that when CCCR <0.01, clinical assessment (prior normal calcium, absence of familial hypercalcemia, renal insufficiency, or repeat testing) was sufficient to exclude FHH in 99% of cases, and only 1% required genetic testing. 2 However, in your scenario—where the biochemical profile is classic for FHH—genetic confirmation is warranted to avoid unnecessary parathyroid surgery.

Why This Is Not Primary Hyperparathyroidism

• Primary hyperparathyroidism typically presents with hypercalcemia (corrected calcium >10.2 mg/dL) and elevated or inappropriately normal PTH. 1
• Urinary calcium excretion in primary hyperparathyroidism is usually normal or elevated (>100 mg/24h), not low. 4, 2
• Low urinary calcium (<100 mg/24h) in the setting of elevated PTH and normal serum calcium is inconsistent with primary hyperparathyroidism and instead points to FHH. 2

Why This Is Not Normocalcemic Primary Hyperparathyroidism (NPHPT)

• NPHPT is defined by persistently elevated PTH with consistently normal albumin‑corrected serum calcium after exclusion of all secondary causes. 1
• Patients with NPHPT typically have normal or elevated urinary calcium (often >200 mg/24h), not low urinary calcium. 1
• Low urinary calcium suggests calcium deprivation (vitamin D or dietary calcium deficiency) or FHH, not NPHPT. 3, 1

Management Recommendations

If FHH Is Confirmed:

• No treatment is required. FHH is a benign condition; parathyroidectomy is contraindicated because it does not cure the hypercalcemia and may cause permanent hypoparathyroidism. 2
• Reassure the patient that FHH does not increase fracture risk, kidney stone risk, or cardiovascular risk. 2
• Screen first‑degree relatives for hypercalcemia and elevated PTH. 2

If FHH Is Excluded and Secondary Causes Are Confirmed:

• Supplement with native vitamin D (cholecalciferol or ergocalciferol) to achieve 25‑hydroxyvitamin D >20 ng/mL (ideally >30 ng/mL). 3, 1
• Ensure adequate dietary calcium intake (1,000–1,200 mg/day). 3, 1
• Recheck serum calcium, PTH, and 24‑hour urinary calcium after 3 months of supplementation. 1 If PTH normalizes and urinary calcium increases, the diagnosis was secondary hyperparathyroidism.

If NPHPT Is Confirmed (After Excluding FHH and Secondary Causes):

• Refer to an endocrinologist and a high‑volume parathyroid surgeon for evaluation. 1
• Surgical indications for NPHPT include: 1
  • Age <50 years
  • eGFR <60 mL/min/1.73 m²
  • Osteoporosis (T‑score ≤−2.5 at any site)
  • Hypercalciuria >300 mg/24h (which is not present in your case)
  • Nephrolithiasis or nephrocalcinosis
  • Disabling neuropsychiatric symptoms (refractory depression, cognitive impairment, "brain fog")
• If surgery is not indicated or declined, monitor serum calcium, phosphorus, and PTH every 3 months. 1

Critical Pitfalls to Avoid

• Do not order parathyroid imaging (ultrasound, sestamibi) before confirming the biochemical diagnosis. 1 Imaging is for surgical planning, not diagnosis, and may lead to unnecessary parathyroidectomy in FHH.
• Do not assume low urinary calcium is due to vitamin D deficiency alone. 4 While vitamin D deficiency can lower urinary calcium, it does not typically reduce it to <100 mg/24h in the presence of elevated PTH unless FHH is present. 2
• Do not supplement with calcitriol or active vitamin D analogs if primary hyperparathyroidism or FHH is suspected. 1 Active vitamin D increases intestinal calcium absorption and can exacerbate hypercalcemia.
• Do not proceed to parathyroidectomy without calculating CCCR and excluding FHH. 2 Surgery in FHH does not cure hypercalcemia and may cause permanent hypoparathyroidism.

Summary of Next Steps

1. Calculate CCCR from spot urine or 24‑hour urine collections. 2
2. If CCCR <0.01, obtain genetic testing for CASR, GNA11, and AP2S1 mutations. 2
3. Confirm vitamin D status (≥20 ng/mL), dietary calcium intake (1,000–1,200 mg/day), and renal function (eGFR ≥60 mL/min/1.73 m²). 1
4. If FHH is confirmed, reassure the patient and avoid surgery. 2
5. If FHH is excluded and secondary causes are identified, supplement with native vitamin D and recheck labs in 3 months. 1
6. If NPHPT is confirmed, refer to endocrinology and surgery for evaluation. 1