Expanding the phenotypic spectrum of variants in PDE4D/PRKAR1A: from acrodysostosis to acroscyphodysplasia

Abstract

Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.

A novel de novo PDE4D gene mutation identified in a Chinese patient with acrodysostosis

“…Moreover, Caroline et al found a heterozygous variant at the same amino acid in PDE4D (p. Tyr677Asp) in a patient with acrodysostosis, suggesting that this tyrosine is critical for PDE4D protein function. However, this article focuses on phenotypic differences with different mutations, and further functional studies were not conducted (Michot et al, ). As a result of complex arrangement and alternative splicing of the PDE4D gene, multiple PDE4D protein variants with distinct N‐terminal sequences including or excluding domains critical for protein function have been identified in humans and in the mouse (Conti & Beavo, ).…”

“…The N‐terminal upstream conserved regions 1 and 2 (UCR1 and UCR2) play crucial roles in forming an auto‐inhibitory domain to partially regulate the catalytic domain (Richter & Conti, ). More than 28 disease‐related PDE4D mutations have been reported to date, almost all of which are located in conserved domains, either in the UCR1, UCR2, or in the catalytic domain (Michot et al, ). It is reasonable to predict that the identified missense p.Y677S mutation positioned in the catalytic domain would affect the function of the protein.…”

“…However, this article focuses on phenotypic differences with different mutations, and further functional studies were not conducted (Michot et al, 2018). As a result of complex arrangement and alternative splicing of the PDE4D gene, multiple PDE4D protein variants with distinct N-terminal sequences including or excluding domains critical for protein function have been identified in humans and in the mouse (Conti & Beavo, 2007).…”

“…The N-terminal upstream conserved regions 1 and 2 (UCR1 and UCR2) play crucial roles in forming an autoinhibitory domain to partially regulate the catalytic domain (Richter & Conti, 2004). More than 28 disease-related PDE4D mutations have been reported to date, almost all of which are located in conserved domains, either in the UCR1, UCR2, or in the catalytic domain (Michot et al, 2018). It is reasonable to predict that the identified missense p. At present, the specific pathogenesis of the disease is still controversial, but it is generally believed that the dysregulation of cAMP levels caused by abnormal enzyme activity could be the underlying mechanism of acrodysostosis that results from PDE4D mutations (Cedervall et al, 2015;Kaname et al, 2014).…”

Novel progressive acrodysostosis‐like skeletal dysplasia, cerebellar atrophy, and ichthyosis

“…Exome testing did not identify mutations in the PDE4D or PRKAR1A genes known to cause acrodysostosis.These mutations can either reduce the amount of RIα protein, with a subsequent depletion of Protein Kinase A(Linglart et al, 2011), or alter the modulation of the levels of cAMP, generating resistance to several hormones(Lee et al, 2012). Individuals with PDE4D related acrodysostosis have a more pronounced midface hypoplasia and intellectual disability compared to PRKAR1A individuals(Michot et al, 2018).Lamellar ichthyosis and hand deformities are reported in psoriatic arthritis but onset is typically later in life. The proband's hand abnormalities and skin findings were present during early childhood and continue to progress during her life.…”