This site is intended for healthcare professionals

Go to /sign-in page

You can view 5 more pages before signing in

Go to /pro/cpd-dashboard page

This page is worth 0.05 CPD credits. CPD dashboard

Go to /account/subscription-details page

This page is worth 0.05 CPD credits. Upgrade to Pro

Familial hypocalciuric hypercalcaemia

Last reviewed dd mmm yyyy. Last edited dd mmm yyyy

Authoring team

Familial hypocalciuric hypercalcaemia (FHH) is a rare autosomal dominant disorder which has been recognised in which there is reduced urinary calcium excretion - less than 200 mg (5mmol) per 24 hours - in the presence of hypercalcaemia (1,2)

  • FHH (3,4,5)
    • caused by inactivating mutations in the calcium sensing receptor (CASR) gene leading to a general calcium-hyposensitivity, compensatory hypercalcaemia and hypocalciuria
      • and less frequently from mutation of GNA11 or AP2S1
      • CASR encodes the calcium-sensing receptors
        • highly expressed on parathyroid cells, where they sense serum calcium concentration and regulate suppression of PTH secretion by serum calcium
          • mutated expression in the kidney in FHH causes increased renal tubular reabsorption of calcium (hypocalciuria)
    • inheritance is autosomal dominant

    • similar to PHPT, FHH is characterized by hypercalcaemia, unsuppressed or elevated plasma parathyroid hormone, and typically normal renal function

    • phenotype is normal, and hypercalcaemic symptoms are generally absent

    • hallmark is a relatively low urine calcium excretion in contrast to PHPT, in which urine calcium excretion is increased

    • vitamin D status as measured by plasma 25-hydroxyvitamin D has been reported to be normal with normal seasonal variations, whereas plasma 1,25-dihydroxyvitamin D has been found slightly increased compared to normal (3)

    • bone mineral density Z-scores are normal in spite of a slightly increased bone turnover

  • differential diagnoses include mainly PHPT, but in some cases also hypercalcaemia of malignancy and use of thiazide diuretics.

In general, FHH does not require treatment (3)

  • a two-step diagnostic procedure is recommended (3)
    • first, the calcium/creatinine clearance ratio is measured from a 24-h urine
    • second, all patients with calcium/creatinine clearance ratio of 0.020 or less are tested for mutations in the CASR gene
      • although has been stated that in familial hypocalciuric hypercalcaemia, Ca/Cr clearance ratio is typically less than 0.01 (2)
    • diagnostic sensitivity of this setup is 98%

NICE suggest to differentiate primary hyperparathyroidism from familial hypocalciuric hypercalcaemia, measure urine calcium excretion using any one of the following tests (4):

  • 24-hour urinary calcium excretion
  • random renal calcium:creatinine excretion ratio
  • random calcium:creatinine clearance ratio.

No treatment is indicated as there is no response to parathyroidectomy. The prognosis is excellent.

There is a very rare autosomal recessive form which is lethal unless parathyroidectomy is performed.

Notes (5):

  • FHH causes lifelong hypercalcemia with features that overlap with typical PHPT
    • incompleteness of this overlap has led to divergent nomenclatures for FHH. I compare two nomenclatures
    • one sets FHH as an entity distinct from PHPT. The other groups FHH with PHPT but conditions FHH as atypical PHPT
      • many FHH features are shared with PHPT and thus support FHH as a form of PHPT. These include a driver mutation expressed mainly in the parathyroid cells. The mutation causes a parathyroid cell insensitivity to extracellular calcium in vivo and in vitro, a right-shift of the set point for suppression of PTH secretion by calcium. Serum PTH is normal or mildly elevated; ie, it is not appropriately suppressed by hypercalcemia
      • some other features are not shared with PHPT and could support FHH as a distinct entity. These include onset of hypercalcemia in the first week of life, frequent persistence of hypercalcemia after subtotal parathyroidectomy, and hypocalciuria
      • the author of this review concluded that the features supporting FHH as a form of PHPT are stronger than those favoring FHH as a distinct entity (5)

Reference:

  1. Famialial hypocalciuric hypercalcaemia. Lancet 1982; 319(8270): 488-489
  2. Younes NA et al. Laboratory screening for hyperparathyroidism.Laboratory screening for hyperparathyroidism. Clin Chim Acta. 2005 Mar;353(1-2):1-12. Review.
  3. Christensen SE et al. Familial hypocalciuric hypercalcaemia: a review.Curr Opin Endocrinol Diabetes Obes. 2011 Dec;18(6):359-70
  4. NICE (May 2019). Primary Hyperparathyroidism
  5. Marx SJ. Familial Hypocalciuric Hypercalcemia as an Atypical Form of Primary Hyperparathyroidism.J Bone Miner Res. 2018 Jan;33(1):27-31

Create an account to add page annotations

Annotations allow you to add information to this page that would be handy to have on hand during a consultation. E.g. a website or number. This information will always show when you visit this page.

The content herein is provided for informational purposes and does not replace the need to apply professional clinical judgement when diagnosing or treating any medical condition. A licensed medical practitioner should be consulted for diagnosis and treatment of any and all medical conditions.

Connect

Copyright 2024 Oxbridge Solutions Limited, a subsidiary of OmniaMed Communications Limited. All rights reserved. Any distribution or duplication of the information contained herein is strictly prohibited. Oxbridge Solutions receives funding from advertising but maintains editorial independence.