One Case Report Of Pseudohypoparathyroidism And Literature Review

BackgroundPseudohypoparathyroidism(PHP)is a group of heterogeneous diseases caused by genetic or epigenetic defects in the GNAS locus,mainly manifesting as end-organ resistance to parathyroid hormone(PTH).The low prevalence of PHP,the difficulty in differentiating between subtypes,and the increasing number of recently reported atypical clinical phenotypes pose difficulties and challenges for clinicians.ObjectivesIn this study,we reported one case of PHP combined with hypokalemia and reviewed literature to summarize its clinical features and molecular genetic features,and to provide information and direction for the subsequent research on this disease.Methods1.In this study,one case data of a patient with PHP combined with hypokalemia was collected and subjected to methylation-specific multiplex ligation-dependent probe amplification(MS-MLPA)and whole-exome sequencing(WES)by extracting peripheral blood.2.We searched PHP-related literature through several Chinese and English databases and reviewed the literature.The groups were divided into PHP1A/C,familial PHP1B and sporadic PHP1B according to PHP typing,and the differences in clinical characteristics between the three groups were compared.The data were statistically analyzed and plotted using IBM SPSS Statistics 26.0 and GraphPad Prism 7.0 software.P<0.05 was considered statistically significant.Results1.Case reportThe patient,a 26-year-old female,was admitted to another hospital in April 2021 with "intermittent tetany for more than 10 years,weakness of both lower extremities for 5 months,and unconsciousness for 1 hour".Laboratory examination indicated elevated PTH,hypocalcemia,hyperphosphatemia and hypokalemia.The MS-MLPA test was performed in our hospital and revealed abnormal methylation in the upstream differentially methylated regions(DMR)of the GNAS gene;no mutation was found in the WES.The patient’s history,laboratory tests and genetic testing led to a final diagnosis of sporadic PHP type 1B and hypokalemia.The patient was treated with oral calcitriol,calcium carbonate D3 tablets,and potassium chloride sustained-release tablets.The patient did not have any further symptoms such as intermittent tetany and weakness.2.Literature reviewBy searching the database,we included a total of 1147 pieces of literature related to PHP from the past 10 years,52 of which were retained after the screening,a total of 121 patients with PHP.(1)These patients were included from 16 different countries,with male predominance(57.85%male vs.42.15%female).The median age of onset in the total population was 12(8,20.5)years,with a higher median age of onset in females than males(P<0.05).(2)In the included cases(52.1%),tetany was the main symptom,and the difference between the three groups was statistically significant(P=0.021).The proportion of tetany in the PHP1A/C group was lower than that in the sporadic PHP1B group(P<0.05).The incidence of Albright s osteodystrophy(AHO)was higher in patients with PHP1A/C than in patients with sporadic and familial PHP1B(all P<0.05).3.4%-23.7%of sporadic PHP1B patients and<18.2%of familial PHP1B patients showed signs of AHO to varying degrees.(3)96%of the patients presented with hypocalcemia and hyperphosphatemia,and the level of PTH was increased in all patients.There was no significant difference in blood calcium,blood phosphorus and PTH among the three groups.The rate of TSH resistance in PHP1A/C patients was higher than sporadic and familial PHP1B patients(all P<0.05).Cranial CT/MR Showed intracranial calcification in 44 cases(69.8%),which was positively correlated with epileptic seizure(r=0.319,p=0.11).Among the included cases,there were 6 patients with hypokalemia,all of which were sporadic PHP1B patients,2 patients with osteoporosis,4 patients with cataract,2 patients with asthma,1 patient with osteoblastic osteosarcoma,2 patients with hypertension,and 1 patient with type 2 diabetes.(4)GNAS frameshift mutations were the most common(31.4%),followed by missense mutations(25.5%),nonsense mutations(13.7%),splice site mutations(5%),synonymous mutations(3.9%),and in-frame deletion mutations(2%).There was a significant difference in the incidence of mental retardation among different mutation types(P=0.001).The proportion of mental retardation in nonsense mutations was higher than that in synonymous mutations,splice site mutations and missense mutations(all P<0.05).All PHP1B patients had one or more aberrant methylation of the GNAS gene,and 3.39%of sporadic PHP1B patients had aberrant methylation secondary to maternal microdeletion of the STX16 gene.3.39%of the methylation abnormalities were affected by the paternal Uniparental isodisomy(iUPD)of chromosome 20,and 54.55%of the GNAS gene methylation abnormalities were secondary to the maternal microdeletion of the STX16 gene.Conclusion(1)Most of the patients with PHP are adolescents,and when adolescent patients present with hypocalcemia seizures with hyperphosphatemia and high levels of PTH,PHP should be considered in parallel with related genetic testing.(2)There are many overlapping clinical phenotypes between PHP1A/C and familial and sporadic PHP 1B patients,and some PHP1B patients may also exhibit varying degrees of AHO signs.Molecular typing is recommended for the definitive diagnosis of patients with PHP,as it facilitates the management and prevention of the disease,and provides accurate genetic and prenatal counseling.(3)In addition to the typical electrolyte disorders(hypocalcemia and hyperphosphatemia),PHP patients can also be combined with hypokalemia.When PHP combined with hypokalemia is present,other diseases causing hypokalemia should be ruled out first to develop the correct treatment plan.