Familial Hypocalciuric Hypercalcaemia
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Direct answer
Familial hypocalciuric hypercalcaemia is a usually benign, autosomal dominant disorder caused by inactivating mutations of the calcium-sensing receptor (CaSR), which resets the calcium set point upwards. Patients have lifelong mild hypercalcaemia with low urinary calcium excretion, and a calcium to creatinine clearance ratio below 0.01 separates it from primary hyperparathyroidism. Because parathyroidectomy rarely cures it, surgery is generally avoided.
What you must remember
- Genetics: inactivating CASR mutations on chromosome 3q, with the heterozygous form common and the homozygous form causing severe neonatal disease.
- Biochemistry: hypercalcaemia with inappropriately normal or only mildly raised parathyroid hormone, which is why PTH alone cannot make the diagnosis.
- Key discriminator: a calcium to creatinine clearance ratio below 0.01 favours familial hypocalciuric hypercalcaemia, while a value above 0.02 favours primary hyperparathyroidism.
- Clinical course: usually asymptomatic and found on routine biochemistry, without the stones, fractures or renal impairment that complicate primary disease.
- Mimics: lithium and thiazide diuretics can produce a similar picture, so the drug history comes first.
- Neonatal form: homozygous infants develop severe hyperparathyroidism that can be life-threatening and needs urgent parathyroidectomy.
- Management: asymptomatic heterozygous adults need reassurance and periodic review, not surgery.
A stepwise test that avoids unnecessary surgery
A 34-year-old woman has a serum calcium of 2.9 mmol/L on routine checks. She feels well, and her father was told in youth that his calcium was high. The question is whether this is primary hyperparathyroidism that needs surgery or a benign inherited trait.
- Confirm and review drugs: Repeat the calcium and check for lithium or thiazide use before anything else.
- Check PTH: An inappropriately normal or mildly raised PTH points away from malignancy and fits either benign or primary disease.
- Measure the clearance ratio: Compare urinary calcium with urinary creatinine, relative to the same ratio in plasma, on a timed or spot urine sample.
- Interpret the value: Below 0.01 favours familial hypocalciuric hypercalcaemia, above 0.02 favours primary disease, and values between need repetition.
- Screen the family: First-degree relatives often carry the same change, and CASR genetic testing helps when the diagnosis stays uncertain.
- Decide against surgery: Avoid parathyroidectomy in the typical heterozygous adult, and reserve it for the neonatal homozygous form.
Where the exam tries to catch you
Most traps come from treating raised calcium as an automatic indication for neck surgery.
- Trap: choosing parathyroidectomy for any hypercalcaemia with a high PTH Correct: primary disease needs surgery, but the urinary clearance ratio must come first because familial hypocalciuric hypercalcaemia rarely responds to it.
- Trap: reading a raised PTH as proof of primary hyperparathyroidism Correct: the benign form can show only mildly raised or normal PTH, so the ratio decides.
- Trap: forgetting lithium or thiazides Correct: both can mimic the benign pattern, and a drug history excludes them before genetic or surgical steps.
Frequently asked questions
Which urinary ratio separates familial hypocalciuric hypercalcaemia from primary hyperparathyroidism?
The calcium to creatinine clearance ratio separates the two conditions, with a value below 0.01 favouring familial hypocalciuric hypercalcaemia and a value above 0.02 favouring primary hyperparathyroidism. Values between these cut-offs fall in a grey zone and need repeat testing alongside a family history. Parathyroid hormone levels alone cannot make the distinction.
Is parathyroidectomy indicated in familial hypocalciuric hypercalcaemia?
Parathyroidectomy is not indicated in the typical heterozygous form, because it rarely normalises calcium. The exception is severe neonatal hyperparathyroidism in homozygous infants, which can be life-threatening and needs urgent surgery. Asymptomatic adults with the benign form should be reassured and monitored.
What genetic defect causes familial hypocalciuric hypercalcaemia?
Familial hypocalciuric hypercalcaemia is caused by inactivating mutations of the CASR gene on chromosome 3q, which encodes the calcium-sensing receptor. Heterozygous mutations give the common autosomal dominant form, while homozygous mutations cause severe neonatal hyperparathyroidism.
Which drugs can mimic familial hypocalciuric hypercalcaemia on biochemistry?
Lithium and thiazide diuretics can raise serum calcium while lowering urinary calcium, mimicking familial hypocalciuric hypercalcaemia. A careful drug history therefore comes before any genetic or surgical assessment. Reviewing the offending drug, where safe, and rechecking calcium clarifies the picture.
Why is the condition called hypocalciuric?
The term describes the low urinary calcium excretion that persists despite high serum calcium. The kidney reabsorbs more calcium because the calcium-sensing receptor, which normally signals calcium excess in the thick ascending limb, is less active. This inappropriately low excretion separates it from most other causes of hypercalcaemia.