The differential diagnosis in FHH is limited to the various aetiologies of PTH- dependent hypercalcaemia, since PTH is not appropriately suppressed for the degree of hypercalcaemia. The distinction between FHH and PHPT is important, given the different management approaches (Table 1). Parathyroid surgery should be avoided in FHH.
Table1. Characteristics of patients with familial hypocalciuric hypercalcaemia type 1– 3 (FHH) and primary hyperparathyroidism (PHPT)
Ten to twenty per cent (10– 20%) of patients with PHPT display a CCCR of < 0.01 [51]. A similar percentage of FHH patients show a value higher than this level. The value of CCCR providing the optimal diagnostic identification between FHH and PHPT was calculated as 0.0115 (Figure 1) similar to the clinically used value of 0.01 which delivers 80% sensitivity and 88% specificity. There is an inverse correlation between the serum calcium and magnesium levels in patients with PHPT. Patients with PHPT and concomitant very low calcium intake, vitamin D deficiency, or mild- to- moderate renal insufficiency, or patients taking thiazide di uretic or lithium therapy can have low CCCR. In the evaluation of PTH- dependent (hypocalciuric) hypercalcaemia, these associated factors should be investigated by thorough history- taking and laboratory tests. Only a few patients have been described in the literature with acquired autoimmune hypocalciuric hypercalcaemia due to antibodies that inactivate or dampen CaSR signalling. Other autoimmune disorders in such patients (Hashimoto’s thyroiditis or celiac sprue) might hint at that diagnosis.
Fig1. Ability of three indices of renal calcium excretion to differentiate between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism. (a) The calcium/ creatinine clearance ratio (CCCR) in patients with familial hypocalciuric hypercalcaemia (FHH, N = 54) and primary hyperparathyroidism (PHPT, N = 97) overlaps considerably, as shown in the two histograms. A CCCR cut- off value of < 0.02 included 98% of the FHH patients in this study, but a group so defined also included 35% of PHPT patients. (b) Scatterplots of 24- h calcium excretion (CE), 24- h calcium/ creatinine excretion (CR) and 24- h CCCR in patients with FHH (N = 54) and PHPT (N = 97) are depicted. Based on overlap analyses, the CCCR misclassified fewer PHPT patients compared to the CE or CR index. Reproduced with permission from Christensen SE, Nissen PH, Vestergaard P, Heickendorff L, Brixen K, Mosekilde L. Discriminative power of t+I294hree 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;69(5):713–20 (48).
In patients with PTH- dependent hypercalcaemia and CCCR < 0.01 or in the CCCR overlap range of 0.01– 0.02 between FHH and PHPT, the diagnosis usually can be made using the family history and bio chemical screening of family members, if appropriate, to demonstrate an autosomal dominant pattern of hypercalcaemia in the patient and in two or more additional family members. Recently, a risk equation named Pro- FHH was developed and tested in two prospective cohorts to predict whether a patient has PHPT. Pro- FHH incorporates the serum calcium, plasma PTH, and serum osteocalcin concentrations, and the calcium- to- creatinine clearance ratio calculated from 24- hour urine collection (24h- CCCR). This approach had a 100% specificity and 100% positive predictive value for the diagnosis of PHPT. This approach correctly categorized 60% of patients in one cohort, and the remainder of patients (40%) was recommended to undergo genetic testing. A prospective trial is necessary to assess its usefulness in a larger population and in patients with elevated PTH concentrations.
In patients with PTH- dependent hypercalcaemia in whom the diagnosis of FHH is suspected, screening for CASR mutations and mutations in AP2S1 codon 15 is appropriate. If the screening is negative, then GNA11 sequencing should be considered. Patients with FHH may not have a family history, either because they may have a de novo mutation and/ or because family members have not been previously studied. Genetic testing should be performed in children less than 10 years old with PTH- dependent hypocalciuric hypercalcaemia, including in children with NHPT and NSHPT and in patients and associated family members with hypocalciuric hypercalcaemia and recurrent pancreatitis. Inactivating CASR mutations have been found in kindreds with familial isolated hyperparathyroidism (FIH) as well. Their clinical presentation could not be differentiated from that of PHPT including at times the presence of hypercalciuria. Parathyroid surgery in such cases of FIH have led to persistent or re current hypercalcaemia in most patients.
