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.

Fig. 1

Scheme of the PRKAR1A gene, modified from Linglart el al. [7]. Above are listed the previously published variants, including the recurrent p.Arg368* variant, which was found in four cases in this study. Below are the four new and unique variants described in this study

Fig. 2

Scheme of the PDE4D gene. Above are listed the previously published variants. Below are the eleven new and unique variants described in this study

Fig. 3

Patients presenting with acrodysostosis. a, b Patient 5; general aspect and hand X-ray. c–e Patient 9; face, hand, and hand X-ray. f–h Patient 15; face, hand, and hand X-ray. Please note on c and f the typical facial gestalt with malar hypoplasia and nasal hypoplasia. Please note on b, e, and h the short broad metacarpals and phalanges, with cone-shaped epiphyses for patient 15

Fig. 4

X-rays of the acroscyphodysplasia cases showing the whole legs, the zoom on the knee and a hand. a–c 1st case. d–f 2nd case. g–i 3rd case. j–l 4th case. m–o 5th case. Please note the cup-shaped metaphyses with embedded epiphyses on knees and the aspect of the hands, similar to the acrodysostosis cases