Introduction: Pseudohypoparathyroidism Type 1a (PHP1a) is a rare disorder caused by mutation in GNAS, which encodes the alpha-subunit of the trimeric stimulatory G protein, Gsα, and links numerous G protein-coupled receptors (GPCR) to adenylyl cyclase. GPCRs are crucial for intracellular endocrine signalling, and since GNAS is expressed predominantly from the maternal allele in some tissues, maternally inherited loss of function GNAS mutations are associated with a highly variable Albrights Hereditary Osteodystrophy (AHO) phenotype. We report a unique Caucasian pedigree with AHO associated with significant thyroid hormone and insulin resistance in all affected members, and with a concomitant diagnosis of inflammatory bowel disease not typically seen in the condition.
Case report: Patient 1 presented aged 2 years, with hypothyroidism, obesity, developmental delay, and lower limb subcutaneous calcifications. Patient 2 presented with neonatal hypoglycaemia (BM 1.0 mmol/l) and developed obesity by 9 months of age (weight >95th percentile, +1.54 SDS). Patient 3 was born at 33/40 (BW 1.88 kg; 31st percentile, −0.51 SDS). Postnatal issues included hypocalcaemia and congenital hypothyroidism. PHP1A due to a mutation in GNAS (c.124C>T, p.R42C) was confirmed in the proband and subsequently each sibling. Pseudopseudohypoparathyroidism (PPHP) was diagnosed in their mother and maternal aunt. Each brother developed classical AHO phenotypes: generalised obesity, short stature (height <0.4th centile), brachydactyly and learning difficulties. Features of hormone resistance (hypothyroidism and insulin resistance) were diagnosed in each child. Their significant hypothyroidism required unusually high doses of levothyroxine (400 μg, 250 μg and 400 μg per day). Severe insulin resistance with acanthosis nigricans and impaired glucose tolerance developed in each child, the latter regressing on metformin with improved glycaemic control. Notably, each child has evidence of inflammatory bowel disease of varying severity.
Conclusion: We report an unusual pedigree with PHP Type 1A in which affected siblings manifest severe thyroid hormone and insulin resistance, and developed inflammatory bowel disease. This case report illustrates the complexity of Gsα signalling disorders and the need for guidelines on screening for associated conditions in managing children with this condition.
22 - 24 Nov 2017
British Society for Paediatric Endocrinology and Diabetes