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Familial Hypocalciuric Hypercalcemia
Introduction
Familial hypocalciuric hypercalcemia (FHH) is a genetic condition characterized by mild hypercalcemia, typically found in otherwise healthy and asymptomatic individuals. Hypercalcemia is a common cause for referral and evaluation in medicine commonly encountered in routine serum chemistry. Differential diagnoses of hypercalcemia are usually based on the acuity and severity of presentation and concomitant level of serum parathyroid hormone (PTH). FHH arises from calcium-sensing receptor gene (CASR) mutations, leading to decreased receptor activity in response to serum calcium levels. This results in mild hypercalcemia, hypocalciuria, hypermagnesemia, and hypophosphatemia, with normal or slightly elevated serum PTH levels.
FHH is usually benign and lacks the severe long-term consequences associated with other hypercalcemia syndromes. The condition's hallmark is an altered calcium-sensing mechanism, making the parathyroid glands less sensitive to calcium and requiring a higher serum calcium level to suppress PTH release. Increased calcium and magnesium reabsorption in the kidneys can also result.[1][2]
Diagnosing FHH can be challenging due to its overlap with primary hyperparathyroidism (PHPT). Diagnostic evaluation usually includes family history, serum chemistry records, and 24-hour urine calcium excretion measurement. A calcium clearance to creatinine clearance ratio (Ca/Cr) of <0.01 is indicative of FHH in most cases. Genetic testing for CASR mutations is recommended in ambiguous cases. While most FHH patients remain asymptomatic, those with symptoms may experience fatigue, weakness, constipation, polyuria, polydipsia, or headaches. FHH typically does not increase fracture risk, although there have been reports of intrauterine bone abnormalities, chondrocalcinosis, and pancreatitis in some patients. Treatment mainly involves patient education and reassurance, with calcimimetic medications like Cinacalcet-HCL or bisphosphonates used in more symptomatic cases despite not being FDA-approved for FHH.
Etiology
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Etiology
The CASR gene is essential in calcium homeostasis and helps maintain a physiological level of ionized calcium in the blood by managing PTH secretion.[3] In most cases, familial hypocalciuric hypercalcemia (FHH) type 1 results from a loss-of-function, heterozygous mutation in the CASR gene on the long arm of chromosome 3.[4][3][2] Those with a homozygous mutation can have severe hypercalcemia with marked neonatal hyperparathyroidism, bone fractures, and failure to thrive.[3][4] More rare cases of familial hypocalciuric hypercalcemia, including FHH type 2 and FHH type 3, are linked to a mutation on chromosome 19.[5][6][7] Most recently, associations have been described between loss-of-function mutation on the GNA11 and missense mutation in the AP2S1 gene with FHH type 2 and FHH type 3, respectively.[8] In exceptional circumstances, FHH can rarely be caused by autoantibodies directed against the calcium-sensing receptor, leading to decreased CASR activity, and should be considered in patients with a strong family history of autoimmune disorders and no other known cause for clinical findings.[3][9]
Epidemiology
FHH is a rare disease inherited in an autosomal dominant pattern and is equally distributed between sexes. FHH has been estimated to be present in 1 in 10,000 to 100,000 individuals, but its prevalence is likely higher given its subclinical nature and challenges to differentiate FHH from PHPT.[2]
Pathophysiology
CASR-expressing tissues include the parathyroid glands, kidneys, bone, thyroidal C cells, and enterocytes.[3][10][11] In the parathyroid gland's chief cells, the CASR controls the synthesis and release of PTH. The CASR is expressed in all nephron segments and affects calcium reabsorption in the kidney.[3] PTH is released from the parathyroid gland when ionized calcium is decreased, leading to increased tubular calcium reabsorption. Hypercalcemia suppresses PTH release and enhances urinary excretion of calcium, sodium chloride, and magnesium independent of PTH and calcitonin levels.[10]
The loss of function mutations in the CASR gene in the parathyroid gland increases the set point for calcium sensing. This makes the parathyroid glands less sensitive to calcium, and a higher-than-normal serum calcium level is required to reduce the PTH release. In the kidney, this defect increases tubular calcium and magnesium reabsorption, resulting in hypercalcemia, hypocalciuria, and frequently high normal levels of serum magnesium.[2]
History and Physical
Most patients with FHH type 1 are usually asymptomatic or have very few symptoms associated with mild hypercalcemia.[12] When symptoms are present, they tend to be nonspecific; patients may report fatigue, weakness, constipation, polyuria, polydipsia, or headaches.[2][4] However, patients with FHH type 3 tend to be more symptomatic, even presenting with hypophosphatemia and osteomalacia in some circumstances.[2]
Normally, the incidence of fractures in FHH type 1 is not increased. Nonetheless, fractures and osteoporosis can still occur.[2][13] Intrauterine bone abnormalities within the same family have also been described in the literature, as well as chondrocalcinosis.[14][15][16] Davis et al reported patients presenting with pancreatitis, but causation has not been established.[17][18] Case reports of children presenting with nephrotic syndrome have also been noted.[19]
Evaluation
Diagnosing FHH can be challenging as the clinical features of FHH and PHPT overlap; however, differentiation between both entities is critical to ensuring adequate management. Obtaining a complete clinical history, including family medical history, is the first step in evaluating FHH. Previous medical records should be reviewed for documented hypercalcemia in serum laboratory testing to establish chronicity and offer guidance since asymptomatic hypercalcemia before the age of 40 usually suggests FHH.[1]
Clinical features suggestive of FHH include a lack of typical hypercalcemic symptoms, mildly elevated calcium level with an "inappropriately" normal or mildly elevated PTH level, a family history of hypercalcemia, or a personal or family history of failed neck exploration.[2][1] However, some patients can present with frank hypercalcemia and elevated PTH.[3][20]
An important diagnostic tool to differentiate FHH from PHPT is the measurement of 24-hour urine calcium excretion with low urinary calcium (<200 mg/24 hours) despite hypercalcemia.[1][20] The calcium clearance to creatinine clearance ratio (or Ca/Cr excretion ratio) is also used to differentiate FHH from PHPT, with a very low value of <0.01 pointing to FHH in 80% to 90% of cases.[1][3][21] About 10% of sporadic PHPT can also have a Ca/Cr ratio of <0.01.[22] Screening for genetic mutations in all patients with a calcium/creatinine clearance ratio of ≤0.020 has been suggested.[2][23]
Differentiation between FHH and PHPT is even more challenging in the absence of family history, when PTH levels are normal, or if the Ca/Cr clearance ratio is >0.01 but <0.02.[21] Even though the age at which hypercalcemia is diagnosed and the family history can guide the final diagnosis, de novo mutations can occur in approximately 15% of FHH cases; absent family history does not necessarily exclude the diagnosis.[21]
Other causes of hypocalciuria should be excluded and corrected if present before urinary calcium is assessed. Vitamin D deficiency, an extremely insufficient calcium intake, renal disease, and treatment with thiazide diuretics or lithium can also falsely decrease urinary calcium levels.[22][24] Another cation, the serum magnesium, is usually in the upper-normal range or mildly elevated in patients with FHH, while the PHPT is usually associated with a low magnesium level.[2][22]
Treatment / Management
Because FHH is usually a benign disorder and, for the most part, patients do not develop complications, education and reassurance of the patient and all affected family members is very important and usually enough to manage FHH.[2] Rarely, in a patient with atypical features and complications, sub-total parathyroidectomy may be indicated.[3](B3)
The CASR itself is a potential therapeutic target in more symptomatic cases. Calcimimetic medications, like Cinacalcet-HCL, have been successfully used in adults and children to stimulate the CASR, mitigating and even sometimes resolving hypercalcemia.[25][26][27] Bisphosphonates have also been used to control hypercalcemia; however, given the chronicity of FHH, they are likely to need repetitive dosing.[25] Clinicians should be aware that the Food and Drug Administration (FDA) has not approved these therapies for treating FHH.(B3)
Differential Diagnosis
FHH should be differentiated from other causes of PTH-dependent hypercalcemia, particularly PHPT. Both PHPT and FHH have elevated serum calcium levels with either inappropriately normal or high serum parathyroid levels; however, PHPT tends to have higher calcium and PTH levels than typically observed with FHH. PHPT is associated with increased urinary calcium, low serum phosphorus, and low magnesium levels. If left untreated, patients are almost certain to develop complications, including constipation, dehydration, nephrolithiasis, chronic kidney disease, and secondary osteoporosis with fractures, to mention some.
FHH can also be hard to differentiate from other etiologies of low urinary calcium, although some might not usually share a high serum calcium level. Poor oral calcium intake and low vitamin D levels can present with low urine calcium and compensatory secondary hyperparathyroidism. Thiazide diuretics decrease renal calcium excretion and may cause mild hypercalcemia, which can sometimes unmask FHH or mild PTHP; however, in normal individuals, PTH levels will be suppressed.
Chronic kidney disease can present a unique challenge, as it can have high PTH levels, high calcium levels, and low urinary calcium if tertiary hyperparathyroidism has developed or if iatrogenic hypercalcemia occurs during the treatment of secondary hyperparathyroidism.[26][27]
Prognosis
In most cases, FHH has a benign disease course and a favorable prognosis with no associated long-term effects, as seen in other hypercalcemia syndromes.[1]
Complications
In the rare cases of homozygous mutation, FHH can present as severe neonatal hyperparathyroidism. Typically, homozygous FHH presents within the first 6 months of life and has features more characteristic of severe PTH-mediated hypercalcemia than FHH. Abnormally high calcium levels can cause dehydration from polyuria; other symptoms can include hypotonia, failure to thrive, and bone changes further complicated by fractures.[3] Fetal intrauterine bone abnormalities in families have also been reported.[14]
In some circumstances, adults can also develop complications from hypercalcemia, especially when levels are moderate 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]
Deterrence and Patient Education
FHH is a rare genetic condition that causes high calcium levels in the blood. The receptor that senses calcium levels in the body needs higher than normal calcium levels to stimulate the parathyroid glands, which release a hormone with the same name that keeps calcium levels within normal levels. FHH is usually a benign condition and, in most circumstances, is not associated with symptoms or other complications typically seen when calcium is high for prolonged periods. In rare circumstances, patients can have complications from high calcium levels, which is usually more pronounced when newborns or infants are affected. Medical treatment or surgery to remove the parathyroid glands may be necessary in patients with complications.
Because FHH is a genetic condition, multiple family members within a family 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 exclude more common causes of high calcium, as indicated.
Pearls and Other Issues
In general, FHH is a nonprogressive benign disorder, rarely associated with complications. The calcium and PTH levels are usually stable over the years. Distinguishing asymptomatic PHPT from FHH is essential, as parathyroidectomy will not routinely cure it. More challenging is to differentiate patients with atypical presentations of either disease and in the absence of family history. Family screening and education are imperative to avoid unnecessary procedures for family members.
Enhancing Healthcare Team Outcomes
Patients with hypercalcemia are frequently seen by nurse practitioners, primary care clinicians, and internists, often after a family member's diagnosis prompts evaluation. Healthcare professionals should be well-versed in FHH to minimize unnecessary tests and procedures. An interprofessional approach is essential, involving endocrinologists for atypical cases and, in rare instances, surgeons for potential parathyroidectomy. Pharmacists are vital in managing medications such as calcimimetic agents or bisphosphonates for severe cases. Geneticists should evaluate patients and their families to confirm the diagnosis, while pediatricians should assess affected children. Effective interprofessional communication and care coordination enhance patient-centered care, improve outcomes, ensure patient safety, and optimize team performance by avoiding redundant and costly monitoring and interventions.
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