Similar clinical and laboratory findings in patients with symptomatic autosomal dominant and sporadic pseudohypoparathyroidism type Ib despite different epigenetic changes at the GNAS locus.

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.