BSPED2021 Oral Communications Oral Communications 4 (9 abstracts)
Pseudohypoparathyroidism type 1A and 1B: presentation, phenotypes and phenotype-genotype associations
Philippa Prentice 1,2 , 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 , Claire Hughes 1 , Caroline Brain 2 , Mehul Dattani 2 & Jeremy Allgrove 2
1Barts Health NHS Trust – Royal London Children’s Hospital, London, United Kingdom; 2Great Ormond Street Hospital for Children, London, United Kingdom; 3Ipswich Hospital, Ipswich, United Kingdom; 4Whittington Health NHS Trust, London, United Kingdom; 5West Middlesex University Hospital, London, United Kingdom
Background & Objective: Pseudohypoparathyroidism (PHP), a heterogeneous condition, classically causes parathyroid hormone (PTH) resistance. PHP1a is caused by heterozygous inactivating mutations on the maternally derived GNAS allele. PHP1b results from methylation defects at the GNAS imprinted gene cluster, which are either sporadic, or familial, normally associated with maternally inherited intragenic STX16 deletions. We investigated the presentation, phenotype, and phenotype-genotype associations of a large PHP cohort.
Method: Casenote review of PHP patients at two UK tertiary centres.
Results: 59 patients were identified, from 45 kindreds; 33 with PHP1a, 26 with PHP1b. PHP1a patients (58% female, 70% White), presented at 3.9+/-6.0 years. 11 presented with hypothyroidism; predominantly with congenital hypothyroidism (n = 8), including 2 with thyroid agenesis. Others mainly presented with hypocalcaemia or were identified by familial testing. There was frequently significant delay from first presentation to diagnosis. Currently, only 72% have PTH resistance but 94% have TSH resistance/hypothyroidism. 6 have GHRH resistance, 2 delayed puberty, 1 precocious puberty. 40% of patients older than 12 years (n = 20) have type 2 diabetes (T2D) or severe insulin insensitivity (average weight only +1.66 SDS). 15 PHP1a patients with GNAS missense variants are of similar weight SDS but shorter (P = 0.004) than those with other variants; they presented later and fewer have PTH resistance (33% vs. 100%) or ossifications. Two patients with frameshift/splicing mutations have progressive osseous heteroplasia (POH). The PHP1b cohort (54% female, 46% White), presented later at 9.4+/-6.5 years (P < 0.05); two thirds with hypocalcaemia. They are taller (P < 0.0005) than PHP1a patients and PTH resistance is more frequent (92%). 32% have TSH resistance. 10 patients with STX16 deletions are heavier (P=0.008), not shorter, than those with sporadic methylation defects. Similar numbers take levothyroxine and alfacalcidol.
Discussion: We describe one of the largest PHP cohorts, reporting notable findings. 25% of PHP1a patients presented with congenital hypothyroidism. POH is not solely seen with paternally derived GNAS mutations but can occur in PHP1a. T2D is commonly seen in young PHP1a patients. Missense variants might cause a milder phenotype, without PTH resistance. A third of PHP1b patients have TSH resistance, with little phenotypic difference between sporadic and familial methylation defects.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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