Testing directed at recognizing FHH among kindreds provisionally diagnosed with FIHP

Several tests of affected individuals from provisionally diag­nosed FIHP kindreds have been utilized to exclude families that might have unrecognized or atypical FHH (Table II). These tests include blood testing of calcium, mag­nesium and PTH levels and determination of renal calcium and creatinine clearance. Review and extension of pedigrees to look for evidence of hypercalcemia in members under the age of 10 improves sensitivity for the detection of FHH, as does CASR gene mutational analysis. Series examining 2 or more FIHP kindreds have found occult CASR gene mutation in some 12% of the total reported fami­lies (Table II). Our own studies found 5 cases of occult CASR mutation among 40 FIHP kindreds (Table I), and Warn­er et al reported 4 cases of CASR mutation in their series of 22 FIHP families.

Interestingly, the index cases and other affected members of CASR mutation-positive kindreds initially considered as FIHP often had clinical features atypical of FHH. For example, probands from 3 of the 5 FIHP kindreds diagnosed as CaSR mutation-positive in our studies were hypercalciuric, as were members of 2 of 4 such kindreds in the Warner et al series. Nephrolithiasis was reported in affected members in 4 of 9 CaSR mutation-positive kindreds initially considered as FIHP in the 2 studies. Two probands presented with intact PTH values >150 pg/ml, more than two times above the value reported to discriminate between FHH and other forms of HPT. Eucalcemia in affected members more than 4 years following subtotal parathyroidectomy, an outcome un­usual among FHH patients, was also reported in 2 of 4 CaSR mutation-positive kindreds initially considered as FIHP. Several clinical findings among affected members supported the diagnosis of FHH in CaSR mutation-positive kindreds ini­tially considered as FIHP, despite the presence of hypercalci- uria and nephrolithiasis in several probands. Hypercalcemic in­dividuals from 3 FIHP kindreds subsequently categorized as CaSR-mutation positive demonstrated mild hypermagnesemia, a finding seen in FHH but not in other forms of familial HPT. Very significant differences were observed when the mean serum magnesium levels among tested hypercal- cemic members of provisionally-diagnosed FIHP kindreds found to be CaSR mutation-positive was compared with that from members of HPT-JT or non-syndromic FIHP kindreds. One CASR mutation-positive kindred initially considered as FIHP revealed clear features of FHH including relative hypocalciuria in other affected members (n = 4), hypercalcemic members less than 10 years old (n = 4), mild hypermagne­semia in hypercalcemic members (n = 4), and persistent hyper- calcemia following subtotal parathyroidectomy (n = 2), even though the proband was hypercalciuric. Some nine different kindreds with a provisional diagnosis of FIHP have been reported in the literature to have germline mu­tations of the CASR gene. As in typical FHH, missense amino-acid substitutions make up the vast majority of germline CASR mutations in kindreds initially considered as FIHP (Table IV). The distribution of missense mutations among the extracel­lular, 7-transmembrane, and intracellular domains of the CASR in these FIHP kindreds does not differ significantly from those in typical FHH families. The R220W CASR mutation in one kindred provisionally diagnosed as FIHP was previously reported in an apparently unrelated typical FHH kindred. The R886P mutation maps to the predicted carboxyl-tail of the CASR; a nearby mutation, F881L, was reported in a kindred with FIHP and including some members with features quite dif­ferent from FHH. Get smart and save money! Buy