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.