tretinoin and Bone-Diseases--Developmental

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 included

Topics: Bone Diseases, Developmental; Child; Chromosomes, Human, Pair 10; Cytochrome P450 Family 26; Gene Expression Regulation, Enzymologic; Humans; Male; Phenotype; Polymorphism, Single Nucleotide; Retinoic Acid 4-Hydroxylase; Tretinoin

Rare, recurrent genomic imbalances facilitate the association of genotype with abnormalities at the "whole body" level. However, at the cellular level, the functional consequences of recurrent genomic abnormalities and how they can be linked to the phenotype are much less investigated.. We report an example of a functional analysis of two genes from a new, overlapping microdeletion of 2p13.2 region (from 72,140,702-72,924,626). The subjects shared intellectual disability (ID), language delay, hyperactivity, facial asymmetry, ear malformations, and vertebral and/or craniofacial abnormalities. The overlapping region included two genes, EXOC6B and CYP26B1, which are involved in exocytosis/Notch signaling and retinoic acid (RA) metabolism, respectively, and are of critical importance for early morphogenesis, symmetry as well as craniofacial, skeleton and brain development. The abnormal function of EXOC6B was documented in patient lymphoblasts by its reduced expression and with perturbed expression of Notch signaling pathway genes HES1 and RBPJ, previously noted to be the consequence of EXOC6B dysfunction in animal and cell line models. Similarly, the function of CYP26B1 was affected by the deletion since the retinoic acid induced expression of this gene in patient lymphoblasts was significantly lower compared to controls (8% of controls).. Haploinsufficiency of CYP26B1 and EXOC6B genes involved in retinoic acid and exocyst/Notch signaling pathways, respectively, has not been reported previously in humans. The developmental anomalies and phenotypic features of our subjects are in keeping with the dysfunction of these genes, considering their known role. Documenting their dysfunction at the cellular level in patient cells enhanced our understanding of biological processes which contribute to the clinical phenotype.

Topics: Abnormalities, Multiple; Adolescent; Bone Diseases, Developmental; Cell Line; Child; Chromosome Deletion; Chromosomes, Human, Pair 2; Craniofacial Abnormalities; Cytochrome P-450 Enzyme System; Developmental Disabilities; Exocytosis; Genotype; GTP-Binding Proteins; Haploinsufficiency; Humans; Male; Oligonucleotide Array Sequence Analysis; Phenotype; Retinoic Acid 4-Hydroxylase; Tretinoin

Prolonged therapy with retinoid drugs (chemically similar to vitamin A) often results in skeletal hyperostoses, similar to those seen in idiopathic skeletal hyperostosis. Eight patients, aged 5-26 years, with dermatologic disorders were treated with 13-cis-retinoic acid. Skeletal surveys were obtained before and during treatment. In 1 year, six of the eight patients had developed such skeletal hyperostoses in both axial and appendicular regions. The cervical spine was the most common site of involvement. None of the children demonstrated accelerated skeletal maturation. Two of the patients had mild musculoskeletal discomfort during this period. The findings indicate that high-dose 13-cis-retinoic acid therapy may cause skeletal hyperostoses, requiring radiographic monitoring during prolonged periods of treatment. An implication of these observations, relating to the etiology of idiopathic skeletal hyperostosis, is discussed.

Topics: Adolescent; Adult; Bone Diseases, Developmental; Child; Child, Preschool; Female; Humans; Isotretinoin; Keratosis; Male; Prospective Studies; Radiography; Spine; Time Factors; Tretinoin