Mutations in Pseudohypoparathyroidism 1a and Pseudopseudohypoparathyroidism in Ethnic Chinese

Abstract

An inactivating mutation in the GNAS gene causes either pseudohypoparathyroidism 1a (PHP1A) when it is maternally inherited or pseudopseudohypoparathyroidism (PPHP) when it is paternally inherited. We investigated clinical manifestations and mutations of the GNAS gene in ethnic Chinese patients with PHP1A or PPHP. Seven patients from 5 families including 4 girls and 2 boys with PHP1A and 1 girl with PPHP were studied. All PHP1A patients had mental retardation. They were treated with calcitriol and CaCO3 with regular monitoring of serum Ca levels, urinary Ca/Cr ratios, and renal sonography. Among them, 5 patients also had primary hypothyroidism suggesting TSH resistance. One female patient had a renal stone which was treated with extracorporeal shockwave lithotripsy. She had an increased urinary Ca/Cr ratio of 0.481 mg/mg when the stone was detected. We detected mutations using PCR and sequencing as well as analysed a splice acceptor site mutation using RT-PCR, sequencing, and minigene construct. We detected 5 mutations: c.85C>T (Q29*), c.103C>T (Q35*), c.840-2A>G (R280Sfs*21), c.1027_1028delGA (D343*), and c.1174G>A (E392K). Mutations c.840-2A>G and c.1027_1028delGA were novel. The c.840-2A>G mutation at the splice acceptor site of intron 10 caused retention of intron 10 in the minigene construct but skipping of exon 11 in the peripheral blood cells. The latter was the most probable mechanism which caused a frameshift, changing Arg to Ser at residue 280 and invoking a premature termination of translation at codon 300 (R280Sfs*21). Five GNAS mutations in ethnic Chinese with PHP1A and PPHP were reported. Two of them were novel. Mutation c.840-2A>G destroyed a spice acceptor site and caused exon skipping. Regular monitoring and adjustment in therapy are mandatory to achieve optimal therapeutic effects and avoid nephrolithiasis in patients with PHP1A.

Clinical and genetic characteristics of Pseudohypoparathyroidism in the Chinese population

“…A total of 23 different mutations in 32 PHP1A and 4 pseudo‐pseudohypoparathyroidism (PPHP) Asian patients have been reported . Our study added 4 new mutations to this list.…”

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement

“…In patients with PHP1A, the average level of TSH is 14.1 ± 10.3 mUI/1, with a range of 1.4 mUI/1 to 46.0 mUI/1 (REFS 24,30,38,67,98,100,117,119,122,123,129,144–146,149,193–205 ) A prompt diagnosis of hypothyroidism after birth and initiation of treatment does not seem to prevent the development of motor or cognitive delay 24 .…”

“…With the exception of PHP1B, a large proportion (around 80% of patients with PHP1A, 50–70% of patients with PPHP and almost all patients with acrodysostosis) of patients with PHP and related disorders have adult short stature 5,13–15,23,24,28,39,45,53,54,62–64,86,89,97,104,105,107,113,122,143,145,146,153,205,206,214–216 Overall the final height deficit in patients with PHP1A and PPHP is severe, approximately −2.5 s.d., with mean heights of 149 cm in women and 155 cm in men 28,122,217 . In patients with PHP1B, despite a great variability in adult height, mean stature is not significantly different from that of the general population 107 .…”

Central Precocious Puberty in a Boy with Pseudohypoparathyroidism Type 1A due to a Novel GNAS Variant, with Congenital Hypothyroidism as the First Manifestation

“…Some PHP1A patients also demonstrate elevated gonadotropin levels which represents gonadotropin resistance ( 8 , 9 , 10 , 11 , 12 ). This finding was mainly reported in female PHP1A patients who presented with either amenorrhea or oligomenorrhea ( 9 , 10 , 11 ). In contrast, male PHP1A patients were rarely reported to have gonadotropin resistance ( 10 , 11 , 12 ).…”