Familial hypocalciuric hypercalcemia

Familial hypocalciuric hypercalcemia (FHH) is an inherited condition that can cause hypercalcemia, a serum calcium level typically above 10.2 mg/dL; although uncommon.[1] It is also known as familial benign hypocalciuric hypercalcemia (FBHH) where there is usually a family history of hypercalcemia which is mild, a urine calcium to creatinine ratio <0.01, and urine calcium <200 mg/day.

Familial hypocalciuric hypercalcemia
SpecialtyEndocrinology, medical genetics

Signs and symptoms

Most cases of familial hypocalciuric hypercalcemia are asymptomatic. Laboratory signs of FHH include:

Causes

Types include:

Name OMIM Locus Gene
HHC1 145980 3q13.3-q21 CaSR
HHC2 145981 19p13.3  ?
HHC3 600740 19q13[2]  ?

Pathogenesis

Most cases of FHH are associated with loss of function mutations in the calcium-sensing receptor (CaSR) gene,[3] expressed in parathyroid and kidney tissue. These mutations decrease the receptor's sensitivity to calcium, resulting in reduced receptor stimulation at normal serum calcium levels. As a result, inhibition of parathyroid hormone release does not occur until higher serum calcium levels are attained, creating a new equilibrium. This is the opposite of what happens with the CaSR sensitizer, cinacalcet. Functionally, parathyroid hormone (PTH) increases calcium resorption from the bone and increases phosphate excretion from the kidney which increases serum calcium and decreases serum phosphate. Individuals with FHH, however, typically have normal PTH levels, as normal calcium homeostasis is maintained, albeit at a higher equilibrium set point. As a consequence, these individuals are not at increased risk of the complications of hyperparathyroidism.

Another form has been associated with chromosome 3q.[4]

Functions of the calcium-sensing receptor
  • Parathyroid gland: mediates negative feedback mechanisms relating to PTH secretion. In normal individuals, PTH secretion decreases with increasing blood calcium levels. Loss of function abnormalities in the CaSR here cause hypercalcemia.
  • Kidneys: mediates negative feedback mechanisms relating to calcium reabsorption from the tubular system. In normal individuals, reabsorption of calcium and other electrolytes decreases with increasing blood calcium level. Loss of function abnormalities in the CaSR here contribute to both hypercalcemia and hypocalciuria.

Diagnosis

As most cases of FHH are asymptomatic and benign, the diagnosis of FHH is less likely to be made. Typically, diagnosis is made in the pursuit of uncovering the etiology of hypercalcemia. Calcium levels are often in the high normal range or slightly elevated. Commonly, the parathyroid hormone level is checked and may be slightly elevated or also on the high normal end. Normally, high calcium should cause low PTH and so this level of PTH is inappropriately high due to the decreased sensitivity of the parathyroid to calcium. This may be mistaken for primary hyperparathyroidism. However, evaluation of urine calcium level will reveal a low level of urine calcium. This too is inappropriate as high serum calcium should result in high urine calcium. If urine calcium is not checked, this may lead to parathyroidectomy for presumed primary hyperparathyroidism

Additionally as the name implies, there may be a family history of benign hypercalcemia.

Ultimately, diagnosis of familial hypocalciuric hypercalcemia is made—as the name implies—by the combination of low urine calcium and high serum calcium.

Treatment

No treatment is generally required, as bone demineralisation and kidney stones are relatively uncommon in the condition.[5]

References
  1. Bletsis, Panagiotis; Metzger, Rosemarie; Nelson, J. Alex; Gasparini, Justin; Alsayed, Mahmoud; Milas, Mira (2022-05-17). "A Novel Missense CASR Gene Sequence Variation Resulting in Familial Hypocalciuric Hypercalcemia". AACE Clinical Case Reports. 8 (5): 194–198. doi:10.1016/j.aace.2022.05.002. ISSN 2376-0605. PMC 9508602. S2CID 248872794.
  2. Lloyd SE, Pannett AA, Dixon PH, Whyte MP, Thakker RV (January 1999). "Localization of familial benign hypercalcemia, Oklahoma variant (FBHOk), to chromosome 19q13". Am. J. Hum. Genet. 64 (1): 189–95. doi:10.1086/302202. PMC 1377717. PMID 9915958.
  3. Schade, David S.; Carroll, Mary F. (May 2003). "A Practical Approach to Hypercalcemia - May 1, 2003 - American Family Physician". American Family Physician. 67 (9): 1959–1966. Retrieved 2009-03-29.
  4. Chou YH, Brown EM, Levi T, et al. (July 1992). "The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families". Nat. Genet. 1 (4): 295–300. doi:10.1038/ng0792-295. PMID 1302026.
  5. "Familial Hypouricemic Hypercalcemia". Archived from the original on 2009-02-24. Retrieved 2009-06-07.
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