Clinical And Genetic Analysis Of Pseudohypoparathyroidism

Background:Pseudohypoparathyroidism(PHP)is a group of diseases which is highly heterogeneous,characterized by parathyroid hormone(PTH)resistance,which is caused by GNAS gene or its upstream molecular abnormalities.PHP is divided into type I and type II according to the abnormal reaction of target organs to PTH before or after the production of c AMP.PHP-Ia,PHP-Ib and PHP-Ic are three subtypes of PHP-I.PHP-Ia is caused by the inactivation mutation of GNAS gene.Generally,patients have many hormones resistance(thyrotropin,gonadotropin,growth hormone releasing hormone,etc.)in addition to PTH resistance.Patients of PHP-Ia have clinical phenotype of Albright hereditary osteodystrophy(AHO)and decreased Gs? activity in vitro.PHPIb is caused by the abnormal methylation of the other four exons upstream of GNAS gene.Patients of PHP-Ib only have PTH resistance or mild TSH resistance,and generally do not have AHO.PHP-Ic patients have similar clinical characteristics to PHP-1b,including AHO and resistance to various hormones.However,in contrary to PHP-Ia,GS? activity is normal in vitro.The incidence rate of PHP is low,and it is easy to be missed and misdiagnosed.Detailed assessment of the clinical characteristics,combined with the detection of GNAS gene mutation will help to improve the diagnosis and treatment of PHP.The present study mainly discussed the clinical characteristics and genetic analysis of a case of pseudohypoparathyroidism and her family members.Methods:A case of pseudohypoparathyroidism and her family members were analyzed retrospectively.The clinical characteristics including phenotype and laboratory tests were discussed.Genomic DNA was extracted from whole blood leukocytes of her family members,and the GNAS gene mutation was analyzed by Sanger sequencing,and the methylation status involving three different methylated regions(DMR)was analyzed by methylation specific polymerase chain reaction(MSP),followed by gene sequencing confirmation.Results:1.Based on the clinical phenotype and laboratory tests,a case of pseudohypoparathyroidism was diagnosed.The patient had hypocalcemia,hyperphosphatemia,hypokalemia,increased serum PTH level,without AHO feature,and thus she was clinically diagnosed as PHP-Ib.No mutation was found in1-13 exons of GNAS gene of this patient.However,loss of the methylation of A / B(also known as 1A)region and the hypermethylation of NESP55 region were detected.2.Parents and younger sister of the patient had no AHO features with normal blood calcium?phosphorus and PTH levels.No mutation in exons,as well no abnormal methylation was found in GNAS gene of the family members.The negative family history and normal GNAS gene test contributed to the diagnosis of a sporadic PHPIb of the patient.3.The patient had hypokalemia accompanied by increased urinary potassium excretion and high plasma renin,thus,PHP-Ib combined with Bartter syndrome was considered.However,genes related to Bartter syndrome were all normal.Conclusion:A patient presented with "hypocalcemia combined with hypokalemia" was finally diagnosed as sporadic PHP-Ib by detail description of clinical characteristics,as well as genetic tests including whole exon sequencing of GNAS and epigenetic modification in GNAS gene in the patient and family members.Molecular diagnosis contributes to the diagnosis and typing of PHP patients.