Familial Hypocalciuric Hypercalcemia: An In-Depth Guide for Healthcare Professionals

Introduction

Familial Hypocalciuric Hypercalcemia (FHH) is a genetic disorder distinguished by mild hypercalcemia, typically observed in individuals who are otherwise healthy and show no symptoms. Hypercalcemia is a frequent reason for medical referrals and evaluations, often detected during routine serum chemistry tests. When assessing hypercalcemia, differential diagnoses are usually determined by the presentation’s urgency and severity, alongside the serum parathyroid hormone (PTH) level. FHH arises due to mutations in the calcium-sensing receptor gene (CASR), leading to reduced receptor activity in response to serum calcium levels. This results in a characteristic combination of mild hypercalcemia, hypocalciuria, hypermagnesemia, and hypophosphatemia, often accompanied by normal or slightly elevated serum PTH levels.

FHH is generally a benign condition, lacking the severe long-term complications associated with other hypercalcemic syndromes. The defining feature of FHH is an altered calcium-sensing mechanism, which renders the parathyroid glands less sensitive to calcium. Consequently, a higher serum calcium level is needed to effectively suppress PTH release. This altered sensitivity contributes to increased reabsorption of calcium and magnesium in the kidneys.[¹][²]

Diagnosing familial hypocalciuric hypercalcemia can be challenging as it shares similarities with primary hyperparathyroidism (PHPT). Diagnostic evaluation typically involves reviewing family history, serum chemistry records, and measuring 24-hour urine calcium excretion. Calculating the calcium clearance to creatinine clearance ratio (Ca/Cr) is particularly useful in differentiating FHH from PHPT; a ratio of <0.01 is highly suggestive of FHH. Genetic testing for CASR mutations is recommended in cases where the diagnosis remains uncertain. While most individuals with FHH are asymptomatic, some may experience non-specific symptoms such as fatigue, weakness, constipation, polyuria, polydipsia, or headaches. It’s important to note that FHH typically does not elevate fracture risk, although there have been reports of intrauterine bone abnormalities, chondrocalcinosis, and pancreatitis in rare cases. Management primarily involves educating and reassuring patients and their families. In more symptomatic cases, calcimimetic medications like cinacalcet or bisphosphonates may be considered, although they are not FDA-approved specifically for FHH.

Etiology of Familial Hypocalciuric Hypercalcemia

The CASR gene plays a crucial role in calcium homeostasis, helping to maintain a stable physiological level of ionized calcium in the blood by regulating PTH secretion.[³] Familial hypocalciuric hypercalcemia (FHH) type 1, the most common form, typically results from a loss-of-function, heterozygous mutation in the CASR gene located on the long arm of chromosome 3.[⁴][³][²] Individuals with a homozygous mutation can present with a more severe phenotype, characterized by marked neonatal hyperparathyroidism, bone fractures, and failure to thrive.[³][⁴] Rarer forms of familial hypocalciuric hypercalcemia, including FHH type 2 and FHH type 3, have been linked to mutations on chromosome 19.[⁵][⁶][⁷] More recently, research has identified associations between loss-of-function mutations in the GNA11 gene and missense mutations in the AP2S1 gene with FHH type 2 and FHH type 3, respectively.[⁸] In rare instances, FHH can be caused by autoantibodies directed against the calcium-sensing receptor, leading to reduced CASR activity. This autoimmune etiology should be considered in patients with a strong family history of autoimmune disorders and no other identifiable cause for their clinical findings.[³][⁹]

Epidemiology of Familial Hypocalciuric Hypercalcemia

Familial hypocalciuric hypercalcemia is considered a rare genetic condition inherited in an autosomal dominant pattern, affecting both sexes equally. Estimates suggest that FHH is present in 1 in 10,000 to 100,000 individuals. However, the true prevalence may be higher due to its often subclinical nature and the challenges in distinguishing FHH from primary hyperparathyroidism (PHPT).[²] The subtle presentation of FHH and its overlap with more common conditions like PHPT can lead to underdiagnosis, suggesting that familial hypocalciuric hypercalcemia may be more widespread than currently recognized.

Pathophysiology of Familial Hypocalciuric Hypercalcemia

Tissues expressing CASR include the parathyroid glands, kidneys, bone, thyroidal C cells, and enterocytes.[³][¹⁰][¹¹] Within the parathyroid gland’s chief cells, CASR regulates the synthesis and release of PTH. The calcium-sensing receptor is also expressed throughout all nephron segments in the kidneys, influencing calcium reabsorption.[³] Parathyroid hormone is released by the parathyroid gland in response to decreased ionized calcium levels, leading to increased tubular calcium reabsorption in the kidneys. Conversely, hypercalcemia suppresses PTH release and promotes urinary excretion of calcium, sodium chloride, and magnesium, independent of PTH and calcitonin levels.[¹⁰]

Image alt text: Illustration depicting the Calcium-Sensing Receptor (CaSR) signaling pathway, highlighting its role in calcium homeostasis and cellular responses.

In familial hypocalciuric hypercalcemia, loss-of-function mutations in the CASR gene within the parathyroid gland elevate the set point for calcium sensing. This diminished sensitivity to calcium means the parathyroid glands require a higher-than-normal serum calcium level to reduce PTH release. In the kidneys, this defect enhances tubular reabsorption of both calcium and magnesium, resulting in the characteristic biochemical profile of hypercalcemia, hypocalciuria, and frequently high-normal serum magnesium levels.[²] This altered calcium handling at both the parathyroid gland and kidney levels contributes to the pathophysiology of familial hypocalciuric hypercalcemia.

History and Physical Examination in Familial Hypocalciuric Hypercalcemia

Most patients with familial hypocalciuric hypercalcemia type 1 are asymptomatic or experience minimal symptoms due to the mild nature of their hypercalcemia.[¹²] When symptoms do occur, they are typically nonspecific. Patients might report fatigue, weakness, constipation, polyuria, polydipsia, or headaches.[²][⁴] However, it’s noted that patients with FHH type 3 tend to be more symptomatic, occasionally presenting with hypophosphatemia and even osteomalacia in some cases.[²]

While the incidence of fractures is generally not increased in FHH type 1, fractures and osteoporosis can still occur in some individuals.[²][¹³] Intrauterine bone abnormalities within families affected by FHH have been documented in medical literature, as well as cases of chondrocalcinosis.[¹⁴][¹⁵][¹⁶] Davis et al. have reported cases of pancreatitis in patients with FHH, although a definitive causal link has not been established.[¹⁷][¹⁸] Furthermore, case reports have described children with familial hypocalciuric hypercalcemia presenting with nephrotic syndrome.[¹⁹]

Evaluation and Diagnosis of Familial Hypocalciuric Hypercalcemia

Diagnosing familial hypocalciuric hypercalcemia can be complex because its clinical features overlap with primary hyperparathyroidism (PHPT). However, accurately distinguishing between these two conditions is crucial for appropriate management. The initial step in evaluating for FHH involves obtaining a thorough clinical history, including a detailed family medical history. Reviewing previous medical records for documented hypercalcemia in serum laboratory tests is important to establish chronicity, as asymptomatic hypercalcemia detected before the age of 40 often suggests FHH.[¹]

Clinical indicators suggestive of familial hypocalciuric hypercalcemia include the absence of typical hypercalcemic symptoms, mildly elevated calcium levels with a PTH level that is “inappropriately” normal or only mildly elevated, a family history of hypercalcemia, or a personal or family history of unsuccessful neck exploration for parathyroidectomy.[²][¹] It’s important to note, however, that some patients can present with frank hypercalcemia and elevated PTH levels.[³][²⁰]

A key diagnostic tool in differentiating FHH from PHPT is the measurement of 24-hour urine calcium excretion. In FHH, urinary calcium excretion is typically low (hypocalciuria). [¹][²⁰] The calcium clearance to creatinine clearance ratio (Ca/Cr excretion ratio) is also used to distinguish between FHH and PHPT, with a very low value of <0.01 strongly indicating FHH.[¹][³][²¹] While approximately 10% of sporadic PHPT cases can also have a Ca/Cr ratio of <0.01, ratios ≤0.020 warrant consideration for genetic screening for CASR mutations.[²][²³]

Differentiation between FHH and PHPT becomes even more challenging when there is no family history of hypercalcemia, when PTH levels are within the normal range, or if the Ca/Cr clearance ratio is >0.01 but <0.02. [²¹] Although the age of hypercalcemia diagnosis and family history are helpful, de novo mutations occur in approximately 15% of FHH cases, meaning the absence of family history does not rule out the diagnosis.[²¹]

It is also important to exclude and correct other causes of hypocalciuria before assessing urinary calcium levels for FHH diagnosis. Vitamin D deficiency, severely insufficient calcium intake, renal disease, and medications such as thiazide diuretics or lithium can falsely lower urinary calcium levels.[²²][²⁴] Another electrolyte, serum magnesium, is often in the upper-normal range or mildly elevated in patients with FHH, while PHPT is typically associated with low magnesium levels.[²][²²]

Image alt text: Diagnostic algorithm outlining steps for evaluating hypercalcemia and differentiating Familial Hypocalciuric Hypercalcemia (FHH) from Primary Hyperparathyroidism (PHPT) based on clinical and laboratory findings.

Treatment and Management of Familial Hypocalciuric Hypercalcemia

Since familial hypocalciuric hypercalcemia is generally a benign condition, and most patients do not develop complications, patient education and reassurance, along with counseling for affected family members, are crucial and often sufficient for management.[²] In rare instances, for patients with atypical features or complications, subtotal parathyroidectomy might be considered.[³]

The calcium-sensing receptor (CASR) itself presents a potential therapeutic target for more symptomatic cases. Calcimimetic medications, such as cinacalcet HCl, have been used successfully in both adults and children to stimulate CASR, effectively mitigating and sometimes resolving hypercalcemia. [25][26][27] Bisphosphonates have also been used to manage hypercalcemia in FHH; however, given the chronic nature of FHH, they would likely require repeated dosing.[²⁵] Clinicians should be aware that these therapies are not currently FDA-approved for the specific treatment of familial hypocalciuric hypercalcemia. The mainstay of management remains patient education and monitoring, with pharmacological interventions reserved for specific, symptomatic cases.

Differential Diagnosis of Familial Hypocalciuric Hypercalcemia

Familial hypocalciuric hypercalcemia must be differentiated from other causes of PTH-dependent hypercalcemia, especially primary hyperparathyroidism (PHPT). Both PHPT and FHH are characterized by elevated serum calcium levels with either inappropriately normal or high serum parathyroid hormone levels. However, PHPT typically presents with higher calcium and PTH levels compared to FHH. PHPT is also associated with increased urinary calcium, low serum phosphorus, and low magnesium levels. Untreated PHPT carries a high risk of complications, including constipation, dehydration, nephrolithiasis, chronic kidney disease, and secondary osteoporosis with fractures.

FHH can also be challenging to distinguish from other conditions causing low urinary calcium, although some of these may not typically present with high serum calcium levels. For example, poor oral calcium intake and vitamin D deficiency can lead to low urine calcium and compensatory secondary hyperparathyroidism, but are less likely to cause hypercalcemia to the degree seen in FHH. Thiazide diuretics reduce renal calcium excretion and can cause mild hypercalcemia, potentially unmasking underlying FHH or mild PHPT. However, in individuals without these conditions, thiazide-induced hypercalcemia will typically suppress PTH levels, differentiating it from FHH.

Chronic kidney disease (CKD) can present a unique diagnostic challenge. CKD can manifest with high PTH levels, high calcium levels, and low urinary calcium, particularly in cases of tertiary hyperparathyroidism or iatrogenic hypercalcemia during the treatment of secondary hyperparathyroidism.[²⁶][²⁷] Careful consideration of the clinical context and comprehensive biochemical evaluation are crucial to differentiate FHH from these other conditions.

Prognosis of Familial Hypocalciuric Hypercalcemia

In most cases, familial hypocalciuric hypercalcemia has a benign disease course and a favorable prognosis, with no associated long-term effects comparable to those seen in other hypercalcemia syndromes.[¹] The mild hypercalcemia characteristic of FHH generally does not lead to significant health complications, and most individuals with FHH can expect a normal lifespan and quality of life.

Complications of Familial Hypocalciuric Hypercalcemia

In rare instances of homozygous mutations, familial hypocalciuric hypercalcemia can manifest as severe neonatal hyperparathyroidism. Typically, homozygous FHH presents within the first 6 months of life and exhibits features more akin to severe PTH-mediated hypercalcemia than typical FHH. Severely elevated calcium levels can cause dehydration due to polyuria. Other symptoms in neonates can include hypotonia, failure to thrive, and bone changes that may be complicated by fractures.[³] Fetal intrauterine bone abnormalities have also been reported in affected families.[¹⁴]

In adults, complications from hypercalcemia can occur in some circumstances, especially when serum calcium levels are moderately to severely elevated (serum calcium >12 mg/dL). Documented complications in the literature include fractures, chondrocalcinosis, nephrolithiasis, arrhythmias, and even pancreatitis.[²][¹⁵][¹⁶][²⁵] However, these complications are less common in typical FHH compared to other causes of hypercalcemia or in the more severe homozygous forms of FHH.

Deterrence and Patient Education for Familial Hypocalciuric Hypercalcemia

Familial hypocalciuric hypercalcemia is a genetic condition causing elevated calcium levels in the blood. The calcium-sensing receptor, responsible for monitoring calcium levels, requires higher than normal calcium concentrations to stimulate the parathyroid glands, which release parathyroid hormone to regulate calcium balance. FHH is typically a benign condition and, in most cases, is not associated with the symptoms or complications commonly seen with prolonged hypercalcemia. In rare situations, patients may develop complications from high calcium levels, particularly newborns and infants. In these cases, medical treatment or parathyroidectomy may be necessary.

Because FHH is a genetic condition, multiple family members can be affected. Therefore, clinical evaluation of blood relatives is recommended when a patient is diagnosed with FHH. Clinicians should discuss abnormal calcium levels with patients and their families, and rule out more common causes of hypercalcemia as appropriate. Educating patients and families about the benign nature of FHH in most cases, and the importance of family screening, are key aspects of management.

Pearls and Other Important Considerations in Familial Hypocalciuric Hypercalcemia

In general, familial hypocalciuric hypercalcemia is a nonprogressive, benign disorder, rarely associated with complications. Calcium and PTH levels usually remain stable over time. Differentiating asymptomatic primary hyperparathyroidism from FHH is essential, as parathyroidectomy is not a curative treatment for FHH and is generally contraindicated. Distinguishing patients with atypical presentations of either disease, especially in the absence of family history, can be more challenging. Family screening and education are crucial to avoid unnecessary procedures for family members who may also have FHH.

Enhancing Healthcare Team Outcomes for Familial Hypocalciuric Hypercalcemia

Patients with hypercalcemia are frequently encountered by nurse practitioners, primary care clinicians, and internists, often prompted by a family member’s diagnosis leading to further evaluation. Healthcare professionals should be well-informed about familial hypocalciuric hypercalcemia to minimize unnecessary diagnostic tests and invasive procedures. An interprofessional team approach is vital, involving endocrinologists for managing atypical cases and, in rare instances, surgeons for considering parathyroidectomy. Pharmacists play a critical role in managing medications like calcimimetic agents or bisphosphonates for severe cases. Geneticists should be involved in evaluating patients and families to confirm the diagnosis and provide genetic counseling. Pediatricians are essential for assessing affected children and managing neonatal presentations. Effective interprofessional communication and coordinated care enhance patient-centered outcomes, improve patient safety, and optimize team performance by avoiding redundant and costly monitoring and interventions.

Review Questions

(Note: Review questions are present in the original article but are not included in this rewritten version as per instructions.)

References

1. Law WM, Heath H. Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families. Ann Intern Med. 1985 Apr;102(4):511-9. [PubMed: 3977197]
2. Lee JY, Shoback DM. Familial hypocalciuric hypercalcemia and related disorders. Best Pract Res Clin Endocrinol Metab. 2018 Oct;32(5):609-619. [PMC free article: PMC6767927] [PubMed: 30449544]
3. Tfelt-Hansen J, Brown EM. The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci. 2005;42(1):35-70. [PubMed: 15697170]
4. Pearce SH, Trump D, Wooding C, Besser GM, Chew SL, Grant DB, Heath DA, Hughes IA, Paterson CR, Whyte MP. Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism. J Clin Invest. 1995 Dec;96(6):2683-92. [PMC free article: PMC185975] [PubMed: 8675635]
5. Heath H, Jackson CE, Otterud B, Leppert MF. Genetic linkage analysis in familial benign (hypocalciuric) hypercalcemia: evidence for locus heterogeneity. Am J Hum Genet. 1993 Jul;53(1):193-200. [PMC free article: PMC1682230] [PubMed: 8317484]
6. Lloyd SE, Pannett AA, Dixon PH, Whyte MP, Thakker RV. Localization of familial benign hypercalcemia, Oklahoma variant (FBHOk), to chromosome 19q13. Am J Hum Genet. 1999 Jan;64(1):189-95. [PMC free article: PMC1377717] [PubMed: 9915958]
7. Michigami T. [Disorders Caused by Mutations in Calcium-Sensing Receptor and Related Diseases.]. Clin Calcium. 2017;27(4):521-527. [PubMed: 28336828]
8. Szalat A, Shpitzen S, Tsur A, Zalmon Koren I, Shilo S, Tripto-Shkolnik L, Durst R, Leitersdorf E, Meiner V. Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia. Endocrine. 2017 Mar;55(3):741-747. [PubMed: 28176280]
9. Pallais JC, Kemp EH, Bergwitz C, Kantham L, Slovik DM, Weetman AP, Brown EM. Autoimmune hypocalciuric hypercalcemia unresponsive to glucocorticoid therapy in a patient with blocking autoantibodies against the calcium-sensing receptor. J Clin Endocrinol Metab. 2011 Mar;96(3):672-80. [PMC free article: PMC3047232] [PubMed: 21159843]
10. Riccardi D, Brown EM. Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Renal Physiol. 2010 Mar;298(3):F485-99. [PMC free article: PMC2838589] [PubMed: 19923405]
11. Chanpaisaeng K, Teerapornpuntakit J, Wongdee K, Charoenphandhu N. Emerging roles of calcium-sensing receptor in the local regulation of intestinal transport of ions and calcium. Am J Physiol Cell Physiol. 2021 Mar 01;320(3):C270-C278. [PubMed: 33356945]
12. Krupinova JA, Almaskhanova AA, Eremkina AK, Bibik EE, Vasilyev EV, Mokrysheva NG. [A series of clinical cases of familial hypocalciuric hypercalcemia syndrome]. Probl Endokrinol (Mosk). 2020 Oct 31;66(5):61-69. [PubMed: 33369373]
13. Mohammed R, Bray MB, Koch CA, Uwaifo GI. Spontaneous rib fractures in a black woman with familial hypocalciuric hypercalcemia. Med Sci Monit. 2008 Oct;14(10):CS102-6. [PubMed: 18830196]
14. Frerot A, Baudouin V, Rideau-Batista A, Couderc A, Garel C, Soltane S, Colella M, Vargas-Poussou R, Hureaux M. Prenatal bone abnormalities in three cases of familial hypocalciuric hypercalcemia. Prenat Diagn. 2022 May;42(5):583-588. [PubMed: 35301736]
15. Volpe A, Guerriero A, Marchetta A, Caramaschi P, Furlani L. Familial hypocalciuric hypercalcemia revealed by chondrocalcinosis. Joint Bone Spine. 2009 Dec;76(6):708-10. [PubMed: 19467900]
16. Alix L, Guggenbuhl P. Familial hypocalciuric hypercalcemia associated with crystal deposition disease. Joint Bone Spine. 2015 Jan;82(1):60-2. [PubMed: 25444087]
17. Davies M, Klimiuk PS, Adams PH, Lumb GA, Large DM, Anderson DC. Familial hypocalciuric hypercalcaemia and acute pancreatitis. Br Med J (Clin Res Ed). 1981 Mar 28;282(6269):1023-5. [PMC free article: PMC1504882] [PubMed: 6783229]
18. Stuckey BG, Gutteridge DH, Kent GN, Reed WD. Familial hypocalciuric hypercalcaemia and pancreatitis: no causal link proven. Aust N Z J Med. 1990 Oct;20(5):718-9, 725. [PubMed: 2285390]
19. Yu M, Xue M, Fan X, Gao C, Xia Z. Nephrotic Syndrome Complicated with Familial Hypocalciuric Hypercalcemia in an Infant: A Case Report and Comprehensive Literature Review. Altern Ther Health Med. 2024 May 03; [PubMed: 38702153]
20. Heath H. Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am. 1989 Sep;18(3):723-40. [PubMed: 2673770]
21. Zajíčková K, Dvořáková M, Moravcová J, Včelák J, Goltzman D. Familial hypocalciuric hypercalcemia in an index male: grey zones of the differential diagnosis from primary hyperparathyroidism in a 13-year clinical follow up. Physiol Res. 2020 Sep 30;69(Suppl 2):S321-S328. [PMC free article: PMC8603734] [PubMed: 33094630]
22. Cetani F, Dinoi E, Pierotti L, Pardi E. Familial states of primary hyperparathyroidism: an update. J Endocrinol Invest. 2024 Sep;47(9):2157-2176. [PubMed: 38635114]
23. Christensen SE, Nissen PH, Vestergaard P, Heickendorff L, Brixen K, Mosekilde L. Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol (Oxf). 2008 Nov;69(5):713-20. [PubMed: 18410554]
24. Ghaznavi SA, Saad NM, Donovan LE. The Biochemical Profile of Familial Hypocalciuric Hypercalcemia and Primary Hyperparathyroidism during Pregnancy and Lactation: Two Case Reports and Review of the Literature. Case Rep Endocrinol. 2016;2016:2725486. [PMC free article: PMC5120212] [PubMed: 27957351]
25. Koca SB. Cinacalcet therapy in a child with novel homozygous CASR p.Glu353Lys mutation causing familial hypocalciuric hypercalcemia type 1: case report and review of the literature. Turk J Pediatr. 2023;65(5):853-861. [PubMed: 37853976]
26. Palumbo VD, Palumbo VD, Damiano G, Messina M, Fazzotta S, Lo Monte G, Lo Monte AI. Tertiary hyperparathyroidism: a review. Clin Ter. 2021 May 05;172(3):241-246. [PubMed: 33956045]
27. Liu J, Tio MC, Verma A, Schmidt IM, Ilori TO, Knauf F, Mc Causland FR, Waikar SS. Determinants and Outcomes Associated With Urinary Calcium Excretion in Chronic Kidney Disease. J Clin Endocrinol Metab. 2022 Jan 01;107(1):e281-e292. [PMC free article: PMC8684460] [PubMed: 34390334]