Accelerated Skeletal Maturation in Disorders of Retinoic Acid Metabolism: A Case Report and Focused Review of the Literature

Abstract

Background Nutritional excess of vitamin A, a precursor for retinoic acid (RA), causes premature epiphyseal fusion, craniosynostosis, and light-dependent retinopathy. Similarly, homozygous loss-of-function mutations in CYP26B1, one of the major RA-metabolizing enzymes, cause advanced bone age, premature epiphyseal fusion, and craniosynostosis. In this paper, a patient with markedly accelerated skeletal and dental development, retinal scarring, and autism-spectrum disease is presented and the role of retinoic acid in longitudinal bone growth and skeletal maturation is reviewed. Method Genetic studies using SNP array and exome sequencing. RA isomers were measured in the patient, family members, and in 18 age-matched healthy children using high-performance liquid chromatography coupled to tandem mass spectrometry. Results A genomic SNP array identified a novel 8.3 megabase microdeletion on chromosome 10q23.2-23.33. The 79 deleted genes included CYP26A1 and C1, both major RA-metabolizing enzymes. Exome sequencing did not detect any variants that were predicted to be deleterious in the remaining alleles of these genes or other known retinoic acid-metabolizing enzymes. The patient exhibited elevated serum total RA (16.5 vs. 12.6 ± 1.5 nM, mean ± SD, subject vs controls) and 13-cisRA (10.7 nM vs. 6.1 ± 1.1). Conclusion The findings support the hypothesis that elevated RA concentrations accelerate bone and dental maturation in humans. CYP26A1 and C1 haploinsufficiency may contribute to the elevated retinoic acid concentrations and clinical findings of the patient, although this phenotype has not been reported in other patients with similar deletions, suggesting that other unknown genetic or environmental factors may also contribute.

Modest Decreases in Endogenous All-trans-Retinoic Acid Produced by a MouseRdh10Heterozygote Provoke Major Abnormalities in Adipogenesis and Lipid Metabolism

“…We undertook this research to reveal postnatal Rdh10 contributions to atRA function and to assess endogenous atRA actions. Previous studies focusing on specific organs or using vitamin A deficiency models revealed that atRA has widespread impact on metabolism, consistent with organ autonomous effects (15)(16)(17)20,(29)(30)(31)(32). Total Rdh10 ablation impairs the biogenesis of multiple organs, including the pancreas, and causes embryonic lethality between E10.5 and E13, but Rdh10 +/2 mice reportedly were "indistinguishable" from WT (33).…”

Functional missense and splicing variants in the retinoic acid catabolizing enzyme CYP26C1 in idiopathic short stature

“…In family 4, the affected son displayed short stature as well as ASD associated with ID, which did not show in his mother. A recent study reported an individual with a de novo 8.3 Mb microdeletion on chromosome 10q23.2-23.33 associated with accelerated skeletal and dental development, craniosynostosis, retinal scarring, and ASD [26]. The patient displayed elevated levels of total RA metabolites.…”

Regulating Retinoic Acid Availability during Development and Regeneration: The Role of the CYP26 Enzymes

“…Raised levels of CYP26 enzymes have also been reported in a range of other cancers including breast, colorectal and head/neck cancers, reviewed [149]. Haploinsufficient microdeletions encompassing the CYP26A1 and CYP26C1-containing chromosomal region has also been reported with differing phenotypes of either optic nerve aplasia or premature skeletal and dental aging combined with retinal scarring and autism [213,214].…”