Dizygotic twins with skeletal dysplasia and resistance to hormones signalling through G protein-coupled receptors and the Gsa/cAMP/PKA pathway-severe craniosynostosis and hypertrophic cardiomyopathy

Abstract

Dizygotic twins had decreased length, rhizomelia and frontal bossing at birth, with elevated TSH levels before commencing thyroxine. Maternal features included round face, short stature, brachydactyly, normal intellect, thyroxine treatment in adulthood, polycystic ovarian syndrome and assisted conception. Twin 1 (male), now 4 years old with developmental delays, developed extensive calcinosis cutis, obesity and growth failure. PTH levels increased until treated with calcium and 1,25-dihydroxyvitamin D3. He is GH deficient, responsive to GH started at age 3 years (likely GHRH resistance). His head shape progressively altered, with CT showing diffuse skull thickening and premature fusion of the coronal, sagittal and lambdoidal sutures with minimal CSF spaces. Twin 2 (female) died at 6 weeks of age due to rapidly progressive hypertrophic cardiomyopathy of unclear aetiology. She was never hypocalcaemic, with no intracardiac calcification at autopsy. Overlap exists in the phenotype of pseudohypoparathyroidism type 1A (PHP1a) (due to maternal heterozygous loss-of-function mutations of Gsa) and acrodysostosis due to gene mutations downstream of Gsa. Acrodysostosis type 1 is due to mutations in PRKAR1A, encoding the cAMP-dependent protein kinase type 1 regulatory subunit protein. Acrodystostosis type 2 is due to mutations affecting PDE4D encoding phosphodiesterase (PDE) 4D, a class IV cAMP-specific PDE. Hormonal resistance, long described in PHP1a has been observed more in acrodysostosis type 1 than 2. The apparent inheritance pattern, phenotypic and radiographic features suggest PHP1a in the twins. Genetic testing is indicated to confirm and hence guide surveillance, as patients with these conditions present specific features, illustrating the unique contribution of Gsa, PRKARIA and PDE4D to the signalling pathway. Craniosynostosis has been described in one case of PHP1a. To our knowledge, hypertrophic cardiomyopathy has not been described in these disorders.L720733832015-11-20 <br />