Objective: Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) carry an identical maternally inherited 3-kb microdeletion up-stream of GNAS (STX16del4-6(mat)), which is associated with a methylation loss restricted to exon A/B. STX16del4-6(mat) is not found in sporadic PHP-Ib (sporPHP-Ib) patients, who show broad GNAS methylation changes. Because of the epigenetic differences between both groups, we searched for clinical and/or laboratory differences.
Patients and methods: Age at diagnosis, calcium, phosphorus and PTH were analysed in 43 patients with AD-PHP-Ib due to STX16del4-6(mat) and in 22 patients with sporPHP-Ib.
Results: All AD-PHP-Ib patients with STX16del4-6(mat) showed only loss of exon A/B methylation. Of the 43 individuals, 26 were symptomatic when diagnosis was established at age 12.1 +/- 1.34 years (mean +/- SEM); laboratory findings at presentation were calcium 1.69 +/- 0.06 mmol/l, phosphorus 2.25 +/- 0.12 mmol/l and PTH 442 +/- 54.1 pg/ml. The remaining 17 individuals with STX16del4-6(mat) were asymptomatic when diagnosed at age 23.5 +/- 3.93 years (calcium 2.18 +/- 0.05 mmol/l, phosphorus 1.63 +/- 0.10 mmol/l, PTH 222 +/- 40.3 pg/ml). Patients with sporPHP-Ib showed methylation changes at two or more GNAS exons, presented at age 10.0 +/- 1.01 years and had, as a group, similar laboratory findings as patients with symptomatic AD-PHP-Ib (calcium 1.51 +/- 0.06 mmol/l, phosphorus 2.65 +/- 0.10 mmol/l, PTH 634 +/- 162.1 pg/ml). However, sporPHP-Ib females appeared to be more severely affected.
Conclusions: Patients with symptomatic AD-PHP-Ib due to STX16del4-6(mat) and sporPHP-Ib have similar changes in calcium, phosphate and PTH. STX16del4-6(mat) often leads to asymptomatic disease and screening of all siblings of affected individuals is therefore advised. The cause of the apparent sexual dimorphism in patients with sporPHP-Ib remains uncertain.