Novel genes in the etiology of FIHP

It is unknown how many as yet unrecognized genotypes may also present as FIHP. Among 76 families initially consid­ered as FIHP in 5 recent clinical studies that investigated for germline MEN1, CASR and HRPT2 gene mutation, 53 families or nearly 70% have no currently recognized syndromic etiology (Table II). Others and we may still be under­estimating the number of non-syndromic FIHP kindreds within this 70% that will ultimately be transferred into 1 of the 3 known syndromic categories. Since the strength of an exclusionary di­agnosis for a syndrome in any family depends on the size of the family, and the degree of thoroughness in the identification and testing of all affected members, it is necessarily more diffi­cult to exclude syndromic diagnoses in smaller kindreds. In our series the number of affected per kindred was smaller in the non-syndromic than the syndromic FIHP subgroups. The number of affecteds was also small in non-syndromic families in other recent FIHP series. This supports the pos­sibility that additional syndromic families have not been identi­fied.

Nevertheless a core subset of non-syndromic kindreds likely will remain even after the future optimization of molecular diag­nostic tools to detect occult MEN1, HPT-JT and FHH-related syndromes. This strongly suggests that novel gene(s) exist whose mutation can result in the FIHP phenotype. If so, then the samples and data collected from the subsets of thoroughly evaluated, apparently non-syndromic FIHP kindreds should as­sist in the identification and characterization of an unknown number of novel genes important for neoplasia in the parathy­roid. Genome-wide linkage analysis of the trait predisposing to HPT among well characterized apparently non-syndromic FIHP kindreds would be a logical starting point in this search.
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