ESPE Abstracts

Background: Nutritional excess of vitamin A, a precursor for retinoic acid (RA), causes premature epiphyseal fusion, craniosynostosis, as well as light-dependent retinopathy. Similarly, homozygous loss-of-function mutations in one of the major RA-metabolizing enzymes CYP26B1 causes advanced bone age, premature epiphyseal fusion, and craniosynostosis. We studied a patient with markedly accelerated skeletal and dental development, retinal scarring, and autism-spectrum disease.

Objective and hypotheses: To characterise and identify the cause of this novel syndrome.

Method: Genetic studies using comparative Genomic Hybridization (CGH) array, and whole exome sequencing. RA metabolites were assessed in patient, family members as well as in ten age-matched boys and ten girls using high-performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS).

Results: The proband is a 10-years-old prepubertal male with bone age advanced 3.5 years over chronologic age. Anterior fontanel was largely closed at age 2 months. Dental age was also markedly advanced with 16 primary teeth present at age 12 months and shedding beginning at age 3 years. Linear growth has been normal along the 50^th percentile since age 3 years. He also has photophobia, chorioretinal scarring, and developmental delay. CGH array identified a novel 8.3 megabase microdeletion on chromosome 10Q23.2-23.33. The 79 deleted genes include CYP26A1 and C1, both major RA metabolizing enzymes. Whole exome sequencing did not detect any variants that are predicted to be deleterious in the remaining copies of these genes, in CYP26B1, or other known RA-metabolizing enzymes. The patient exhibited elevated serum levels of total RA (16.5 nM vs 12.6±2.9; patient vs controls (mean±2 S.D.)) and 13-Cis RA (10.7 nM vs 6.1±2.2; patient vs controls (mean±2 S.D.)).

Conclusion: The findings of elevated total RA and 13Cis RA support the hypothesis that elevated RA levels accelerate bone and dental maturation in humans. CYP26A1 and C1 haploinsufficiency may contribute to the elevated RA levels, although this phenotype has not been reported in other patients with similar heterozygous deletions, suggesting that other unknown genetic or environmental factors may also contribute.

Funding: The work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health. AD received funding from NICHD, project number 5K23HD073351. ON is supported by the Swedish Research Council (project 2012-99X-221998–01-3 and K2015-54X-22736-01-4) and Karolinska Institutet.