All reported kindreds so far with the phenotype of FIHP that have undergone successful linkage analysis have had their trait linked to either the MEN1 locus on 11q13, the HPT-JT locus on 1q25-31, the CASR gene locus on 3q, or FHH-related but unknown gene loci on 19p and 19q. These families each had available for genetic analysis at least 7 affected members or obligate gene carriers, the lower limit of cases necessary to give a significant linkage score. The small number of affected individuals precludes genetic linkage in many non-syndromic FIHP families. Because of the less frequent expression of non-parathyroid features in HPT-JT compared to MEN1, a larger proportion with the former syndrome might be expected to present as FIHP. Yet the combined data from surveys of provisionally diagnosed FIHP kindreds shows occult cases of MEN1 are identified about twice as often as HPT-JT (Table II). This may be due in part to problems of initial kindred ascertainment. As discussed above, consideration of mostly younger affected members at the time of kindred ascertainment may obscure the initial recognition of MEN1 and lead to a provisional diagnosis of FIHP. This is because HPT is usually the earliest and most penetrant feature of MEN1. Another reason for the unexpectedly low number of incomplete expressions of HPT- JT recognized among FIHP kindreds might be the low sensitivity of current PCR-based HRPT2 gene mutation testing methods.
The prevalence of FHH-related disorders may also be underestimated in studies of provisionally diagnosed FIHP kindreds. No mutation in the CASR gene has been demonstrated in the probands from as many as 1/3 to 1/2 of kindreds with FHH trait linked to chromosome 3q. Furthermore a small number of FHH kindreds have a trait that is not linked to the CASR locus at chromosome 3q. Thus germline DNA screening of the CASR gene is helpful but is not presently a definitive tool to rule out FHH. For these reasons and because relative hypocalciuria is not always present in each affected member of CASR mutation-positive kindreds, it is likely that the prevalence of FHH-related syndromes is underestimated in current analyses of FIHP kindreds.
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