Familial hypocalciuric hypercalcaemia

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