The Characteristics Of Bone Turnover Index In Patients With Pseudohypoparathyroidism Type 1 Of Different Molecular Subtypes

BackgroundPseudohypoparathyroidism?PHP?is a rare and heterogeneous disease,caused by mutations and methylation changes in the GNAS on maternal allele,leading to target organs resistance to PTH.The main subtypes of PHP 1 is 1A/C,sporadic 1B and familial1B.Previous evidence from BMD or X-ray imaging suggested that excessive serum parathyroid hormone?PTH?may act on skeletal tissue,whereas bone responsiveness to PTH in different PHP1 subtypes is still controversial.ObjectivesTo assess bone turnover status among different subtypes of PHP 1 patients and compare wtih non-surgical hypoparathyroidism?NS-HP?patients by bone turnover markers?BTMs?,to investigate skeletal responsiveness to PTH in a large cohort of PHP 1 patients.MethodsA total of 63 PHP1 patients diagnosed by molecular analysis were recruited from 2012 to 2017 at the department of endocrinology,Peking Union Medical College Hospital.Fourty-eight gender-and age-matched nonsurgical hypoparathyroidism?NS-HP?patients were selected and included for comparison.The clinical manifestations and laboratory examinations were collected respectively for all subjects.BTMs including serum ?-CTX and ALP were measured by chemiluminescent immunoassay and multichannel automatic biochemical analyzer,respectively.BTMs and related parameters were compared among subtypes of PHP 1 patients,and between PHP1 and NS-HP patients,respectively.Longitudinal observation of 22 PHP1 patients with regular treatment was performed.Linear regression was performed to identify independent predictors of serum ?-CTX and ALP respectively in PHP1 patients.ResultsA total of 63 PHP1 patients were identified,including 15 PHP1A/C,14 familial PHP1B and 34 sporadic PHP1B patients.Three GNAS mutations were discovered by whole exome sequencing,namely NM₀01077490.2:c.1247G>A?p.Arg416Gln?,NM₀00516.4:c.195dup?p.Asn66*?and NM₀00516.4:c.296T>A?p.Leu99Gln?.The median serum ?-CTX and ALP levels in PHP1 patients were 0.52?0.10-3.20?ng/ml and 105?46-588?U/L,respectively.There were 23.8%patients with high BTMs for all PHP1.There was no statistical difference on ?-CTX between different subtypes of PHP 1 patients,even after adjusting for differences in age,sex,BMI and treatment.While the ALP level in PHP1A patients was lower than that in PHP1B patients?84?49-313?U/L vs 109?46-588?U/L,p=0.03?,but the difference was not significant in adult group after stratified by age.The serum ?-CTX level was positively correlated with serum PTH level for all PHP1 patients,PHP1B and PHP1A separately?B=0.001,0.001 and 0.004,all p<0.05?by multiple linear regression analysis.The serum ALP level was also independently positively related with serum PTH level for all PHP1 patients.BTMs levels of PHP1 patients were significantly higher than those in age-and gender-matched NS-HP patients??-CTX:0.56ng/ml vs.0.20ng/ml,p=0.001;ALP:105U/L vs.72 U/L,p=0.001?,and these differences still existed in adults patients.After stratified by age,?-CTX level in adult PHP1A,sporadic PHP1B and familial PHP1B patients were all higher than those in NS-HP patients statistically.Longitudinal observation was achieved in 22 patients.At the second evaluation,the PTH and BTMs significantly decreased after regular treatment of calcium and vitamin D agents.Meanwhile change of serum PTH was positively correlated with changes in ?-CTX and ALP after adjusting for serum Ca levels and treatment interval?p-CTX:r=0.507,p=0.023;ALP:r=0.475,p=0.034?.ConclusionsIn this group of relatively large single-centre series of PHP1 patients classified accurately based on molecular analysis,the characteristics of bone turnover markers and theirs association with PTH levels in different subtypes of PHP1 were analyzed.BTMs including serum ?-CTX and ALP in both PHP1A and PHP1B patients were significantly correlated with PTH levels and significantly higher than those of NS-HP patients,supporting the skeletal response to PTH in both in PHP1B and PHP1A patients.Therefore,it is reasonable to monitor PTH and BTMs in addition to serum and urinary calcium levels in the follow-up of all PHP1 patients.Furthermore,to normalize PTH levels may help to avoid adverse effects of elevated PTH on bone when treating not only PHP1B but also PHP1A.