tretinoin and Growth-Disorders

Prolonged cis-retinoic acid (RA) exposure contributes to premature epiphyseal closure. cis-RA is administered in various treatment regimens for pediatric cancers, thus increasing the risk for bone deformities and compromised growth.. We present a case of premature epiphyseal closure in a 9-year-old female with a history of medulloblastoma and treatment with a multimodal regimen including cis-RA. She was subsequently diagnosed with radiation-induced endocrine late effects including hypothyroidism and growth hormone deficiency (GHD). Seven months after initiation of GH therapy, an increased prominence of the wrists and knees combined with a deceleration in growth velocity prompted further evaluation; radiographs revealed bilateral premature closure of the distal femur and proximal tibia growth plates despite normal left wrist bone age.. High doses of vitamin A and its analogs are linked to premature closure of the lower-extremity growth plates in animals and children. Pediatric brain tumor patients are at increased risk of growth failure due to concurrent radiation-induced GHD, damage to the spinal bones, and cis-RA-associated premature closure of the lower-extremity growth plates, with significant reduction in adult stature. A better appreciation of the detrimental effect of cis-RA on the growing skeleton is needed to monitor at-risk patients and to provide timely interventions.

Topics: Adult; Bone Diseases; Child; Female; Growth Disorders; Growth Plate; Human Growth Hormone; Humans; Lower Extremity; Medulloblastoma; Tretinoin

Mutations in the homeobox gene SHOX cause SHOX deficiency, a condition with clinical manifestations ranging from short stature without dysmorphic signs to severe mesomelic skeletal dysplasia. In rare cases, individuals with SHOX deficiency are asymptomatic. To elucidate the factors that modify disease severity/penetrance, we studied a three-generation family with SHOX deficiency. The variant p.Phe508Cys of the retinoic acid catabolizing enzyme CYP26C1 co-segregated with the SHOX variant p.Val161Ala in the affected individuals, while the SHOX mutant alone was present in asymptomatic individuals. Two further cases with SHOX deficiency and damaging CYP26C1 variants were identified in a cohort of 68 individuals with LWD The identified CYP26C1 variants affected its catabolic activity, leading to an increased level of retinoic acid. High levels of retinoic acid significantly decrease SHOX expression in human primary chondrocytes and zebrafish embryos. Individual morpholino knockdown of either gene shortens the pectoral fins, whereas depletion of both genes leads to a more severe phenotype. Together, our findings describe CYP26C1 as the first genetic modifier for SHOX deficiency.

Topics: Adolescent; Adult; Aged; Animals; Child; Cytochrome P450 Family 26; Female; Gene Expression Profiling; Genetic Predisposition to Disease; Genetic Variation; Growth Disorders; Homeodomain Proteins; Humans; Male; Middle Aged; Osteochondrodysplasias; Retinoic Acid 4-Hydroxylase; Sequence Analysis, DNA; Severity of Illness Index; Short Stature Homeobox Protein; Tretinoin; Young Adult; Zebrafish; Zebrafish Proteins

The postimplantation embryos of rodents have been particularly convenient to study in culture using the whole embryo culture (WEC) system developed by New. Two serious limitations of the method will be illustrated in the present paper and proposals will be made to improve the quality of the information. The first limitation is that the developmental period amenable to culture has not been significantly extended in recent years. In the present paper, we show that the culture of mouse presomitic stages for 48 h leads to poorly reproducible results and frequent dysmorphogenic embryos. We also show that early somite stages cultured for 54 h or less have a normal growth and differentiation. In contrast, the culture of these embryos for 72 h results in subtle abnormalities of the head and the first branchial arch. The second limitation is that the gross morphology and histology are often not informative enough to distinguish between overall toxicity and developmental toxicity. We suggest some improvements by the association of WEC with two specific techniques: 1) whole-mount immunostaining of sensory ganglia and nerves and 2) in situ hybridization on histological sections using molecular probes for some developmental genes. Embryos reaching about the 30 somite stage at the end of the culture were processed for whole-mount immunostaining of sensory ganglia and nerves. We show that these structures are very sensitive to the noxious effects of HgCl2 and valproate. Both developmental retardations and dysmorphogeneses of the cervical ganglia and nerves were observed. Embryos were also exposed in vitro to low concentrations of all-trans-retinoic acid (AT-RA) and processed for in situ hybridization with radiolabeled anti-sense RNA probes for the Hoxb-1 and Hoxb-2 developmental genes. Three-dimensional reconstructions of the expression domains were performed. The data show that AT-RA induces ectopic expression domains of Hoxb-1. Our experiments demonstrate that techniques such as immunostaining and in situ hybridization can significantly expand the information obtained from whole postimplantation embryo culture.

Topics: Animals; Congenital Abnormalities; Culture Techniques; Embryo, Mammalian; Embryonic and Fetal Development; Embryonic Development; Female; Gene Expression; Growth Disorders; Homeodomain Proteins; Immunoenzyme Techniques; In Situ Hybridization; Mercuric Chloride; Mice; Morphogenesis; Pregnancy; Time Factors; Transcription Factors; Tretinoin; Valproic Acid

Null mutant mice for retinoic acid receptor gamma 2 (RAR gamma 2) or all RAR gamma isoforms were generated. RAR gamma 2 mutants appeared normal, whereas RAR gamma mutants exhibited growth deficiency, early lethality, and male sterility due to squamous metaplasia of the seminal vesicles and prostate. These defects were previously observed in vitamin A-deficient animals and could be prevented by RA administration, demonstrating that RAR gamma mediates some of the retinoid signal in vivo. Congenital defects included Harderian gland agenesis, tracheal cartilage malformations, and homeotic transformations along the rostral axial skeleton, establishing a direct link between RA and patterning of the axial skeleton. We also show that in utero RA-induced lumbosacral truncations are mediated by RAR gamma. The observed RAR gamma null phenotype suggests a high degree of functional redundancy among the RARs. The variable penetrance of some of the observed defects is discussed in light of this redundancy and stochastic variation of gene activity.

Topics: Abnormalities, Multiple; Animals; Base Sequence; Bone and Bones; Carrier Proteins; Cartilage; Embryonic and Fetal Development; Female; Genes, Lethal; Growth Disorders; Homozygote; Male; Mice; Mice, Mutant Strains; Molecular Sequence Data; Receptors, Retinoic Acid; Recombination, Genetic; Tretinoin; Vitamin A Deficiency

Diffuse lichen planus, a rare disorder in children, was observed in an 8-year-old boy. Effective therapy in this disease remains a problem and currently relies predominantly on the use of the corticosteroids. The complications attendant with corticosteroid administration in children are discussed and a review of alternate modes of therapy for lichen planus is presented.

Topics: Adrenal Cortex Hormones; Adrenal Insufficiency; Child; Griseofulvin; Growth Disorders; Humans; Lichen Planus; Male; Pruritus; PUVA Therapy; Tretinoin; Vitamin A