Background: Acrodysostosis is a rare skeletal dysplasia with severe brachydactyly, facial dysostosis and nasal hypoplasia. Some patients show hormone resistance whose phenotypes are similar to pseudohypoparathyroidism (PHP). In 2012, PRKAR1A gene was identified as one of the responsible genes of Acrodysostosis with hormonal resistance (ADOHR). Generally, brachydactyly is severe and hormone resistance is mild in Acrodysostosis patients.
Objective and hypotheses: To report a novel heterozygous mutation of PRKAR1A gene in an ADOHR patient with mild brachydactyly.
Method: Mutational analyses: We sequenced three genes associated in PHP using the next generation sequence strategy. Functional assay: We generated PRKAR1A expression vectors containing wild type and mutant type. Using the constructs, we are going to perform CRE-Luciferase activity to analyse the Protein Kinase A activity.
Case: A 5-year-old boy who presented with short stature was referred to our hospital. He had mild brachydactyly and undescended testis of right side. Mild TSH and PTH resistance were shown; TSH 8.649 μIU/ml, fT3 3.95 pg/ml, fT4 1.25 ng/dl, iPTH 95 pg/ml, Ca 9.7 mg/dl and P 4.8 mg/dl. Urinary cAMP sharply elevated after injection of PTH, while urine P did not. Phenotypical features suggest PHP, but the response to PTH indicates an abnormality in the downstream of GNAS.
Results: We identified a novel heterozygous mutation of c.511G>A, p.G171R in PRKAR1A gene. G171 is highly conserved among PRKAR1A protein. G171 is located in cAMP-binding domain B. Only one patient with severe brachydactyly is reported to carry mutation in the cAMP-binding domain B.
Conclusion: This is the first report of ADOHR patient who carry PRKAR1A mutation with mild brachydactyly. Our finding expands the phenotypic features of PRKAR1A gene mutations.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology