ESPE2021 ePoster Category 1 Bone A (10 abstracts)
Characterisation and phenotype-genotype associations of a large cohort of patients with pseudohypoparathyroidism type 1A and 1B
Philippa Prentice 1 , Louise Wilson 2 , Evelien Gevers 1,2 , Jackie Buck 3 , Joseph Raine 4 , Jayanti Rangasami 5 , Helen McGloin 5 , Catherine Peters 2 , Rakesh Amin 2 , Hoong-Wei Gan 2 , Caroline Brain 2 , Mehul Dattani 2 & Jeremy Allgrove 2
1Royal London Hospital - Barts Health NHS Trust, London, United Kingdom; 2Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom; 3Ipswich Hospital, Ipswich, United Kingdom; 4Whittington Health NHS Trust, London, United Kingdom; 5West Middlesex University Hospital, London, United Kingdom
We characterised the phenotype of PHP patients at two UK tertiary care centres and investigated phenotype-genotype correlations.
Method: Retrospective review of case notes for patients with PHP at two UK tertiary care centres.
Results: 55 patients, from 41 kindreds, were identified; 32 with PHP1a, 23 with PHP1b. The PHP1a cohort (56% female, 69% White), currently aged 16.7+/-10.6 years, presented at age 3.9+/-6.1 years; the majority with hypothyroidism (n = 11, half as neonates), familial testing (n = 6), AHO (n = 5) or hypocalcaemia (n = 5). 94% have TSH resistance/hypothyroidism and 72% PTH resistance. Additionally, 6 have GHRH resistance, 1 had precocious puberty and 2 were treated for delayed puberty. Of 20 patients older than 12 years, 40% have type 2 diabetes or severe insulin insensitivity (average weight 1.66 SDS); another patient has acanthosis nigricans. Of 32 patients with PHP1a, 14 have GNAS missense variants and are shorter (P = 0.002) but of similar weight SDS (P = 0.2) to those with other variants; fewer have PTH resistance (36% vs 100%,p=0.0006); they presented later and fewer have ossifications. Two patients with splicing/frameshift mutations have progressive osseous heteroplasia (POH). The PHP1b cohort (52% female, 39% White), currently aged 17.1+/-7.5 years, presented later at 8.2+/-4.3 years (P < 0.05); two thirds with hypocalcaemia. They are taller than those with PHP1a (P < 0.0005), with no difference in weight SDS. PTH resistance is more frequent (91%). 35% have TSH resistance. 10 patients with STX16 deletions and methylation defects only in GNAS exon 1A/B are heavier (P = 0.006) than those with sporadic methylation defects. Similar numbers are on alfacalcidol and levothyroxine.
Discussion: This is one of the largest PHP cohorts reported to date and presents several notable findings. A large proportion of PHP1a patients have T2D or insulin insensitivity, even without obesity. POH is not confined to paternally derived GNAS mutations and can be associated with PHP1a. Missense variants may cause a milder phenotype, and more likely to be associated with hypothyroidism without PTH resistance. One third of our PHP1b patients have TSH resistance, with little phenotypic difference between sporadic and familial gene abnormalities.
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