ESPE Abstracts (2019) 92 P2-48

Novel Mutation of the Prkar1a Gene in a Girl with Clinical Diagnosis of Pseudohypoparathyroidism

Alma Toromanovic1, Marta Elli Francesca2, Giovanna Mantovani2

1Department of Pediatrics, University Clinical Center Tuzla, Tuzla, Bosnia and Herzegovina. 2Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit; Department of Clinical Sciences and Community Health, Milan, Italy

Introduction: Despite the high detection rate of GNAS molecular defects, about 30% of patients with a clinical suspect of PHP/AHO still lack a confirming molecular diagnosis. Mutations in genes encoding proteins crucial for cAMP-mediated signaling have been recently detected in a small subset of patients negative for GNAS defects, showing a phenotypic overlap between PHP and Acrodysostosis.

Clinical case presentation: We report on a case of acrodysostosis associated with mutation in the PRKAR1A gene in a girl with a clinical diagnosis of PHP1A. Our female patient was born as the second child of healthy unrelated parents at 38 weeks of gestation by caesarian section following a pregnancy complicated by oligohydramnion with birth weight 2,120 g and lenght 51 cm. A 6-year-old girl was referred to our pediatric endocrinology clinic for obesity. Physical examination revealed broad face, widely spaced eyes, maxillonasal hypoplasia, small broad hands and feet, and subcutaneous ossifications at her right leg. Her weight was 25 kg (90th percentile), height 112,3 cm (25th to 50th percentile), and body mass index was 19,8 (>97th percentile). Radiography of the hands and feet showed brachydactyly and cone-shaped epiphyses. Celiac disease was diagnosed at the age of 6,5 years. Resistance to TSH was documented by increased TSH (9,6 mIU/L) with normal thyroxine level, absence of anti-thyroid antibodies and presence of normal thyroid scan at the age of 6,5 year. Hormonal resistance to PTH was documented at the age of 9 years, as indicated by increased PTH level (129 pg/ml) in the presence of normale serum calcium (2,4 mmol/L) and increased serum phosphate (1,8 mmol/L). The presence of genetic/epigenetic defects affecting GNAS locus had been excluded. After the age of 10 progressive growth failure with lack of pubertal spurt was documented. No behavioral disorders, nor learning disability were noticed. According to the growing knowledge on Gsα-cAMP signaling-linked disorders, screening of PRKAR1A and PDE4D in a large series of patients clinically diagnosed with PHP1A/AHO but negative for GNAS defects was done. Sanger sequencing analysis of coding exons 2-11 in our patient unraveled a previously undescribed heterozygous missense variant (c.625A>G) affecting exon 7.

Conclusion: The molecular and clinical overlap among these Gsα-cAMP signaling-linked disorders indicates the need for different classification models and for a deeper investigation of the mechanisms through which defects of the cAMP signaling cascade cause either common or specific clinical phenotypes in order to elaborate patient-specific algorithms.

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