Clinical Characteristics And Genetics Of Pseudohypoparathyroidism In Children

ObjectiveThe clinical and genetic characteristics of 16 patients with pseudohypoparathyroidism were summarised to improve clinicians’ understanding of the disease and reduce the rate of misdiagnosis.Method1.Data were collected from patients clinically diagnosed with pseudohypoparathyroidism in the Department of Pediatrics,First Affiliated Hospital of Guangxi Medical University from January 2015 to December 2020.2.Patients were subjected to medical whole-exome testing(including GNAS,PRKAR1 A,PDE4D/3A and PTH1 R genes)using next-generation sequencing technology to screen out gene sequences with variants matching the clinical phenotype,and Sanger sequencing was performed to validate and analyze the pathogenicity of the variant sequences;as well as applying methylation multiplex-linkage-dependent probe amplification technology to perform GNAS gene Methylation detection.3.The clinical features,genetic characteristics and treatment experience of the disease were analysed and summarised.Result1.Sixteen patients with clinically diagnosed pseudohypoparathyroidism: 9males and 7 females,mean age of onset 5 years(2-12.4 years),mean duration4.6 years(1 week-10.6 years);clinical symptoms were mostly epileptiform seizures(13 cases,81.3%)and hand-foot convulsions(7 cases,43.8%),of which6(37.5%)had been misdiagnosed as The other 14(87.5%)had the Albright hereditary osteodystrophy phenotype,9(56.3%)had clinical/subclinical hypothyroidism and 12(75.0%)had mental retardation;laboratory tests showed low blood calcium,high blood phosphorus and elevated blood parathyroid hormone.Intracranial calcification was noted in 13(81.3%)patients.All patients were treated with calcium and phosphorus elevation using osteotriol,calcium and a low phosphorus diet,as well as individualised levothyroxine sodium supplementation for the combined clinical hypothyroidism.2.Among the 10 patients who underwent genetic testing,six GNAS gene variants were detected.Five PHP-Ia/Ic patients had one nonsense mutation(c.723＿724ins TG)and four code-shifting mutations(two c.2494＿2497del GACT,one c.1159 del A,and one c.565＿568del CTGA),respectively.c.2494＿2497del GACT(p.Asp832 Metfs Ter14),c.1159 del A(p.Met387fs),c.723＿724ins TG(p.Thr242Ter)have not been reported in the literature.one case of PHP-Ib type patient had extensive methylation abnormalities of GNAS gene due to paternal haploid diploidy.Conclusion1.PHP is a rare genetic disease with a high rate of misdiagnosis at first diagnosis.Patients with a convulsive onset should consider the possibility of PHP and have blood calcium,blood phosphorus,and blood parathyroid hormone tests performed as early as possible to assist in identification.2.PHP typing is complex and genetic testing including GNAS gene methylation status analysis is performed to aid in clinical typing.3.Treatment with osteotriol and calcium can be effective in improving the condition,while other phenotypes such as hypothyroidism should be treated individually.4.GNAS genes c.2494＿2497del GACT,c.1159 del A,c.723＿724ins TG are the first reported pathogenic mutations in PHP.