Endocrine Abstracts (2019) 65 OP4.2 | DOI: 10.1530/endoabs.65.OP4.2

Identification of novel pathogenic variants and phenotypic features in patients with pseudohypoparathyroidism and acrodysostosis, subtypes of the newly defined inactivating PTH/PTHrP signalling disorders (iPPSD) classification system

Adam Truelove1, Akhilesh Mulay1, Matina Prapa2, Ruth Casey3, Amanda Adler3, Amaka Offiah4, Kenneth Poole5, Jamie Trotman2, Namir Al Hasso2 & Soo-Mi Park2

1School of Clinical Medicine, University of Cambridge, Cambridge, UK; 2East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK; 3Wolfson Diabetes and Endocrine Clinic, Department of Endocrinology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK; 4University of Sheffield, Academic Unit of Child Health, Sheffield Children's NHS Foundation Trust, Sheffield, UK; 5Department of Rheumatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK

Due to overlapping clinical and biochemical features, disorders now known to be molecular defects in the parathyroid hormone (PTH)-receptor signalling pathway, such as Albright Hereditary Osteodystrophy (AHO), pseudohypoparathyroidism (PHP), and acrodysostosis, have been historically confused. AHO is a complex disorder defined by the presence of a short adult stature relative to the height of an unaffected parent and brachydactyly type E, as well as a stocky build, round face, and ectopic calcifications. PHP describes end-organ resistance to PTH, occurring with or without the physical features of AHO. PTH resistance was initially considered an obligatory manifestation of AHO, with the terms AHO and PHP used interchangeably. However, it was later recognised that AHO can occur in the absence of PTH resistance, termed pseudopseudohypoparathyroidism (PPHP). PHP and PPHP are aetiologically linked and caused by genetic and/or epigenetic alterations in the guanine nucleotide-binding protein alpha-stimulating (Gsα) locus (GNAS) in chromosome 20q13. Acrodysostosis, a less-recognised group of skeletal dysplasias, partially overlap with skeletal, endocrine, and neurodevelopmental features of AHO/PHP, and can be overlooked in clinical practice, causing confusion in the literature. Acrodysostosis is caused by defects in two genes, PRKAR1A and PDE4D, both encoding important components of the Gsα-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signalling pathway. Here we describe the clinical course and genotype of two adult patients with overlapping AHO features who harboured novel pathogenic variants in GNAS (c.2273C>G, p.Pro758Arg, NM_080425.2) and PRKAR1A (c.803C>T, p.Ala268Val, NM_002734.4), respectively. The cases of these two patients highlight the value of expert radiological opinion and molecular testing in establishing correct diagnoses, and we discuss phenotypic features of our patients, including the first description of subcutaneous ossification and spina bifida occulta in PRKAR1A-related acrodysostosis, in the context of the novel inactivating PTH/PTH related peptide (PTHrP) signalling disorder (iPPSD) classification system.