title: Accelerated Skeletal Maturation in Disorders of Retinoic Acid Metabolism: A Case Report and Focused Review of the Literature.
abstract: 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. Genetic studies were carried out 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. A genomic SNP array identified a novel 8.3 megabase microdeletion on chromosome 10q23.2-23.33. The 79 deleted genes includedCYP26A1andC1, 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 plasma 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). 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.
authors: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors: O
authors: O
authors: Nilsson
authors: Department of Pharmaceutics School of Pharmacy, University of Washington, Seattle, WA, USA.
authors: N
authors: N
authors: Isoherranen
authors: Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
authors: M H
authors: MH
authors: Guo
authors: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors: J C
authors: JC
authors: Lui
authors: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors: Y H
authors: YH
authors: Jee
authors: Harold Schnitzer Diabetes Health Center, Oregon Health and Science University, Portland, OR, USA.
authors: I
authors: I
authors: Guttmann-Bauman
authors: Department of Paediatrics, University of Cambridge, Cambridge, UK.
authors: C
authors: C
authors: Acerini
authors: Department of Ophthalmology, Columbia University, New York, NY, USA.
authors: W
authors: W
authors: Lee
authors: Department of Ophthalmology, Columbia University, New York, NY, USA.
authors: R
authors: R
authors: Allikmets
authors: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors: J A
authors: JA
authors: Yanovski
authors: Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: A
authors: A
authors: Dauber
authors: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors: J
authors: J
authors: Baron
mesh_terms: D001848:Bone Diseases, Developmental / Q000235:genetics / Q000473:pathology*; D002648:Child; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D000072500:Cytochrome P450 Family 26 / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000072516:Retinoic Acid 4-Hydroxylase / Q000235:genetics*; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D014212:Tretinoin; C000607078:CYP26A1 protein, human; C482075:CYP26C1 protein, human; D000072500:Cytochrome P450 Family 26; D000072516:Retinoic Acid 4-Hydroxylase