Endocrine Abstracts

Patients affected by pseudohypoparathyroidism type 1b (PHP-1b) develop resistance to PTH leading to hypocalcemia and hyperphosphoremia, which is often associated with resistance to TSH. PHP-Ib is associated with methylation changes at one or several differentially methylated regions (DMRs) within the GNAS complex locus, located at 20q13.2–13.3. This locus gives rise to several different transcripts (NESP55, XL, A/B), with varying patterns of expression depending on the parental allele and the methylation status of the specific exon 1 promoters.

PHP-Ib may follow an autosomal dominant pattern of maternal inheritance associated with deletion in STX16 or it can arise sporadically.

Epigenetic changes observed in genomic DNAs from sporadic PHP-Ib mimic the paternal-specific methylation pattern without maternal epigenetic marks.

Uniparental disomy (UPD) is a condition in which a chromosomally disomic individual inherited both copies of a chromosome from one parent only. Thus, paternal UPD20 is a plausible cause of PHP-1b.

We screened a cohort of 57 unrelated patients presenting with sporadic PHP-1b and broad GNAS epigenetic changes to evaluate the frequency of patUPD20.

Comparative genomic hybridization (CGH) combined with SNP-array (Agilent 4×180K sureprint G3 Cancer) was used to identify copy number variant and loss of heterozygosity (LOH). Single nucleotide polymorphisms or short tandem repeats were studied along chromosome 20 in the proband and compared to his two parents to confirm LOH.

Because GCH arrays required high quality DNA only 20 samples were tested.

We found four patients (20%) with patUPD20: two patients with complete patUPD, one patient with patUPD of the long arm of chromosome 20 and one patient with a large interstitial UPD20 including GNAS locus. We also detailed the phenotype and the DNA methylation pattern of these patients.

This study suggests that patUPD20 is a frequent cause of PHP-1b that should be tested in the evaluation of patients with sporadic PHP-1b.