Background: Sporadic pseudohypoparathyroidism type Ib (spor-PHP-Ib) is caused by GNAS methylation alterations with loss of imprinting at the exon A/B differentially methylated region (DMR), without genetic deletions disrupting the STX16 ICR. These patients classically display hormone resistance limited to PTH and TSH with no Albright hereditary osteodistrophy (AHO).
Objective and hypotheses: We describe two cases with the same imprinting methylation defect, but different clinical presentation.
Method: Patient (pt) 1 was first evaluated for suspicious neurologic disease presenting with vertigo, eye lateral deviation and diplopia. He underwent brain computed tomography that did not show cerebral infarction or expansive lesion, but basal ganglia calcifications. He showed high PTH levels, severe hypocalcemia and hyperphosphatemia. TSH levels were slightly elevated. Pt 2 was firstly evaluated for slipped capital femoral epiphysis (SCFE) at 6 years of age and severe osteoporosis. She showed high PTH levels, normal calcium levels, but hyperphosphatemia. TSH was in normal range. Both cases did not show AHO. Therefore PHP-Ib was suspected and confirmed by molecular analysis.
Results: Our patients share the same methylation abnormality on the GNAS gene locus, however they differ in phenotype expression. We hypothesized that our patients probably have different bone sensitivity to PTH, higher in case 2. According to this theory, prolonged (unrecognized) hypocalcemia led to basal ganglia calcification in case 1; higher bone PTH sensitivity led to normal calcium serum levels, with secondary osteoporosis and SCFE in case 2. Interestingly all cases with PHP Ib with SCFE reported by literature are females.
Conclusion: Our two cases differed in clinical features, while showing comparable genotypes, and confirming that the long-term effects of elevated PTH on bone are still controversial in these patients and they may be related to other factors.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology