ESPE Abstracts

Background: Albright hereditary osteodystrophy (AHO) is a rare constellation of dysmorphic physical features such as short stocky build, round face, cutaneous ossification, and metacarpophalangeal abnormalities as well as pseudohypoparathyroidism (PHP) with variable hypocalcemia, and hyperphosphatemia. This hereditary metabolic disorder is caused by a mutation in the GNAS1 gene in the q13.11 region of chromosome 20.

Case Report: We describe a 6 year old female who presented with low satiety, obesity and developmental delay and was initially diagnosed with primary hypothyroidism at 8 months of age (TSH 9mU/l, FT4 11.2). Thyroid antibodies were negative and a trial off levothyroxine at age 4 years showed worsening thyroid function (TSH 12.2 mU/l, FT4 10.3 pmol/l) and levothyroxine was re-started. Despite normalisation of her thyroid function with treatment, her weight remained on the 99.6^th centile. Her hyperphagia was a consistent feature and her weight was maintained due to extensive family efforts. Her bone profile was normal (cCa 2.32 mmol/l, P 1.76 mmol/l, vitamin D 94.7 nmol/l), but she had persistently raised PTH (26.6 pmol/l), confirming pseudohypoparathyroidism (PHP). Her height was on the 91^st centile, which is atypical in PHP. Initial genetic investigations (CGH array, Prader Willi syndrome methylation studies, genetics of obesity research study, trio whole exome sequencing) were unremarkable until her mother was noted to be short and have short 4^th and 5^th metacarpals during a clinic appointment. Re-referral to the genetic team with re-analysis of the original sample assuming the mother had the same condition identified a maternally inherited GNAS mutation 7 years later. The mother had a milder phenotype with normal biochemical picture (cCa 2.36 mmol/l, P 1.36 mmol/l, vitamin D 51.9 nmol/l, PTH 3.5 pmol/l).

Conclusion: We discuss the journey to diagnosis as it is often delayed owing to lack of recognition of the syndrome and associated features. Our case also highlights the importance of clinical review of parents for the interpretation of trio whole exome or genome sequencing. In all rare clinical presentations maintaining an open mind and reviewing the history and examination is essential in reaching the correct diagnosis, in this case not only in the patient, but also in her mother.