Search

Internationally, there have been isolated case reports published of children presenting with dilated cardiomyopathy (DCM) in the setting of undiagnosed rickets. Although there has been an increased prevalence of rickets in the United States, there has been only one documented case of associated DCM. At our institution, a hospital database search was conducted from year 1997 to year 2007 to identify patients with confirmed vitamin D deficiency in addition to DCM. Through this search, four exclusively breast-fed African American infants were identified. These infants presented with congestive heart failure secondary to DCM and, at their admission, were found to have laboratory evidence consistent with hypocalcemic rickets. These patients responded dramatically to treatment with vitamin D and calcium, and cardiac function returned to normal within months. Early recognition of vitamin D deficiency was an important factor in these patients' clinical course. These case reviews present a rare, serious complication of vitamin D-deficient rickets and support evidence for prevention of this nutritional deficiency with vitamin D supplementation in exclusively breast-fed infants.

Chemotherapy-related growth failure is a significant problem in children with acute lymphoblastic leukemia (ALL) and other childhood cancers. Growth impairment after cranial radiation (CR) can result in diminished adult height, but growth failure following chemotherapy without CR is usually followed by catch-up growth and normal adult height.1 A retrospective review of 347 ALL survivors registered in our Long Term Follow Up (LTFU) Clinic, since 1997 revealed that 109 had received CR; 3, total body irradiation (TBI); and 235, neither CR nor TBI. For patients whose growth velocity slowed, growth hormone (GH) levels and pediatric endocrinology referrals were obtained. Among the 112 ALL survivors who had received some form of CR, 5 had significant growth failure with growth hormone deficiency (GHD). Among the 235 ALL survivors treated with chemotherapy without CR, 2 were diagnosed with growth failure and GHD. We report the two survivors of childhood ALL treated with chemotherapy without CR who required GH replacement due to absence of catch-up growth. A 15-year-old boy and a 12-year-old girl, off therapy for 9 and 6 years, respectively, were evaluated for decreased growth velocity and failure of catch-up growth. Peak GH responses to stimulation using arginine and clonidine were 3.4 and 3.0 ng/ml, respectively (normal >10 ng/ml). Other causes of growth failure were ruled out, and GH replacement therapy was instituted. Their chemotherapy had included methotrexate, 6 mercaptopurine, vincristine, adriamycin, cyclophosphamide, L-asparaginase, dexamethasone, cytarabine, 6 thioguanine, and intrathecal methotrexate. The growth of all children treated with intensive chemotherapy, regardless of whether CR was administered, should be closely monitored with measurement of standing height at 6 months intervals until growth is complete.

The estrogen receptor (ER) is a ligand-dependent transcription factor which regulates growth, development, differentiation and reproduction. To test the hypothesis that the diverse effects of the ER could be mediated by interacting with other transcription factors/oncogenes, the present study assessed its interaction with the tumor suppressor p53. p53 is a transcription factor which is involved in cell cycle regulation and apoptosis. We found that the wild-type p53 physically interacted with ER in vivo and repressed the estrogen-activated transcriptional activity. However, p53 mutants had no or reduced repression effect, depending on the sites of mutation. These findings suggest that p53 can cross talk with the ER in hormone-activated signaling pathways in cells.

The aromatase inhibitor, fadrozole hydrochloride (CGS 16949A), was developed for the treatment of breast cancer, and has not been available for pediatric use because of the lack of information about potential reproductive toxicology. To determine the effect of fadrozole on subsequent fertility and reproductive performance in rats, peripubertal male and female Sprague-Dawley rats (10/group) were given fadrozole by oral gavage once a day for 60 consecutive days (age 21 through 80 d) at a dose of 0, 1200, or 6000 micrograms/kg/d (dose range in women with breast cancer: 60 to 240 micrograms/kg/d). Following a 30-d recovery period (days 81 through 111 of age), cohabitation with untreated rats of the opposite sex was accomplished for 30 d or until positive evidence of mating was obtained (daily vaginal smears). The nonfadrozole-treated males used for cohabitation were proven fertile breeders; the females were virgin with proven 4-d estrous cycles. The duration of pregnancy, number, sex, condition, and body weight of pups were determined. Pregnant rats were weighed on gestational days 7, 14, and 20. There was a profound decrease in the number of estrous cycles at both dose levels of fadrozole compared to the control (P0.001). During the 30-d recovery period, estrous cycles were reestablished within a few days in the treated rats and the number and length of estrous cycles were not statistically different between fadrozole-treated and control rats. The gestational body weights of fadrozole-treated and untreated females did not differ significantly. There were no statistically significant differences in the number of matings/number of pairings, gestational length, mean live pups/litter, % pups born alive/litter, and % male pups/litter in the three groups (vehicle-, low-, and high-dose fadrozole-treated females, cohabited with untreated males and fadrozole-treated males, cohabited with untreated females). Thus, young male and female rats treated for 60 d with large doses of fadrozole had no detectable adverse effect on subsequent reproductive function.

Because of therapeutic advances over the past 50 years, long-term survival is now a reality for nearly 80% of children and adolescents diagnosed with cancer. The growing population of childhood cancer survivors is notable for its vulnerability to adverse health outcomes, many of which may not become clinically apparent until years after therapy completion. Early detection, prevention, and ameliorative interventions provide the opportunity to reduce cancer-related morbidity and mortality. This review is intended to complement the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. The objective of this review is to familiarize readers with the diverse health risks experienced by childhood cancer survivors that stem from the heterogeneous therapeutic interventions required to achieve disease control.

We administered the aromatase inhibitor fadrozole to 16 girls with gonadotropin-independent precocious puberty due to the McCune-Albright syndrome. The girls’ ages ranged from 3.2–9.7 yr, and their bone ages ranged from 5.75–14.25 yr. After baseline evaluations, fadrozole was started at a dose of 240 μg/kg·d (equivalent to the dose recommended for therapy of estrogen-dependent breast cancer) for 12–21 months and increased to 480 μg/kg·d for an additional 12 months in 10 girls. During treatment, seven girls had evidence of central precocious puberty; hence, the GnRH agonist deslorelin (4 μg/kg·d sc) was added to their regimen. One girl was on a long-acting GnRH agonist from the start of treatment. Patients were evaluated at 2–6-month intervals throughout treatment. After the first 6–12 months of treatment, fadrozole showed some benefits in 10 girls, including decrease in frequency of menses and/or rates of linear growth and bone maturation; however, fadrozole had no significant benefit in the group as a whole. The seven girls with evidence of central precocious puberty had no slowing in the progression of their puberty during the combined fadrozole and GnRH analog treatment. Adverse effects of fadrozole included inhibition of cortisol and aldosterone biosynthesis at the dose of 480 μg/kg·d, without clinical evidence of adrenal insufficiency. In addition, three patients complained of nonspecific abdominal pain during fadrozole treatment. In one patient, this resolved with a reduction in dose from 480 to 240 μg/kg·d; in two patients, it resolved spontaneously. One girl had muscle weakness and constipation on the 480 μg/kg·d. This resolved after discontinuation of the drug. We conclude that fadrozole is not sufficiently potent to block estrogen synthesis in most girls with gonadotropin-independent precocious puberty due to the McCune-Albright syndrome and may impair the adrenocortical stress response.

Estrogen receptors regulate transcription of genes essential for sexual development and reproductive function. Since the retinoid X receptor (RXR) is able to modulate estrogen responsive genes and both 9-cis RA and fatty acids influenced development of estrogen responsive tumors, we hypothesized that estrogen responsive genes might be modulated by RXR and the fatty acid receptor (peroxisome proliferator-activated receptor, PPAR). To test this hypothesis, transfection assays in CV-1 cells were performed with an estrogen response element (ERE) coupled to a luciferase reporter construct. Addition of expression vectors for RXR and PPAR resulted in an 11-fold increase in luciferase activity in the presence of 9-cis RA. Furthermore, mobility shift assays demonstrated binding of RXR and PPAR to the vitellogenin A2-ERE and an ERE in the oxytocin promoter. Methylation interference assays demonstrated that specific guanine residues required for RXR/PPAR binding to the ERE were similar to residues required for ER binding. Moreover, RXR domain-deleted constructs in transfection assays showed that activation required RXR since an RXR delta AF-2 mutant completely abrogated reporter activity. Oligoprecipitation binding studies with biotinylated ERE and (35)S-labeled in vitro translated RXR constructs confirmed binding of delta AF-2 RXR mutant to the ERE in the presence of baculovirus-expressed PPAR. Finally, in situ hybridization confirmed RXR and PPAR mRNA expression in estrogen responsive tissues. Collectively, these data suggest that RXR and PPAR are present in reproductive tissues, are capable of activating estrogen responsive genes and suggest that the mechanism of activation may involve direct binding of the receptors to estrogen response elements.

To evaluate the relative usefulness of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) in screening for GH status, GH stimulation (arginine-insulin/L-DOPA) tests and overnight GH studies (every 20 min sampling) were performed in 104 healthy short children (32 girls), aged 3-16 yr (height, -1.8 or more SD). IGFBP-3 had no advantage over IGF-I in screening sensitivity or specificity. IGF-I correlated with mean nighttime GH. Both IGF-I and IGFBP-3 correlated with peak stimulated GH. To identify more than 90% of children with GH deficiency (GHD) and borderline GHD, the mean values for age for IGF-I and IGFBP-3 were required as the cut-off criterion. However, at this criterion, 70% or more of idiopathic short stature (ISS) children would have to undergo testing to identify 90% of GHD or borderline GHD. More stringent criteria (-1.0, -1.64, and -2.0 SD) were more specific, but lost sensitivity. A practical application is suggested. Screening use of IGF-I with criterion of -1.0 SD would identify a subgroup that includes 88% of GHD, 71% of borderline GHD, and 46% of ISS. Both IGF-I and IGF-BP-3 higher than -1.0 SD would accurately identify 68% of ISS as not needing GH testing. Evaluation of growth velocity would identify the remaining children requiring definitive testing. Thus, combined screening for GHD using both IGF-I and IGFBP-3 has no better sensitivity than either test alone. However, such combined screening will improve the specificity and thus decrease the number of normal but short children who might otherwise undergo unnecessary testing.

Di(2-ethylhexyl) phthalate (DEHP) is used to make polyvinyl chloride (PVC) plastic tubing soft and flexible. Animal data show that adverse effects of DEHP exposure may include reduced fertility, reduced sperm production in males, and ovarian dysfunction in females. Known treatments that involve high DEHP exposures are blood exchange transfusions, extracorporeal membrane oxygenation (ECMO), and cardiovascular surgery. Although potential exposure to DEHP in ECMO patients is significant, the exposure has not been associated with short-term toxicity. To evaluate long-term toxicity, we undertook a study of neonatal ECMO survivors to assess their onset of puberty and sexual maturity. We evaluated 13 male and 6 female subjects at 14-16 years of age who had undergone ECMO as neonates. All subjects had a complete physical examination including measurements for height, weight, head circumference, and pubertal assessment by Tanner staging. The testicular volume and the phallic length were measured in male participants. Laboratory tests included thyroid, liver, and renal function as well as measurements of luteinizing hormone, follicle-stimulating hormone, testosterone for males, and estradiol for females. Except for one patient with Marfan syndrome, the rest had normal growth percentile for age and sex. All had normal values for thyroid, liver, and renal functions. Sexual hormones were appropriate for the stage of pubertal maturity. Our results indicate that adolescents exposed to significant quantities of DEHP as neonates showed no significant adverse effects on their physical growth and pubertal maturity. Thyroid, liver, renal, and male and female gonadal functions tested were within normal range for age and sex distribution. Key Words: DEHP, ECMO, toxicity.

Zeta-crystallin/quinone reductase (CRYZ) is an NADPH oxidoreductase expressed at very high levels in the lenses of two groups of mammals: camelids and some hystricomorph rodents. It is also expressed at very low levels in all other species tested. Comparative analysis of the mechanisms mediating the high expression of this enzyme/crystallin in the lens of the Ilama (Lama guanacoe) and the guinea pig (Cavia porcellus) provided evidence for independent recruitment of this enzyme as a lens crystallin in both species and allowed us to elucidate for the first time the mechanism of lens recruitment of an enzyme-crystallin. The data presented here show that in both species such recruitment most likely occurred through the generation of new lens promoters from nonfunctional intron sequences by the accumulation of point mutations and/or small deletions and insertions. These results further support the idea that recruitment of CRYZ resulted from an adaptive process in which the high expression of CRYZ in the lens provides some selective advantage rather than from a purely neutral evolutionary process.

Publisher Summary This chapter discusses a study suggesting that an estrogen-responsive DNA element (ERE) can be specifically activated by cotransfection of the retinoid X receptor (RXR) and peroxisome proliferator-activated receptors (PPAR) in the absence of the estrogen receptor (ER). The specific nucleotide sequence of the ERE differs from the canonical RXR and PPAR element in the orientation and number of nucleotide spaces between half-sites of the element. The cotransfection of RXR and PPAR caused an augmentation of ERE-dependent reporter activity in the presence or absence of either 9-cis-RA or arachidonic acid. Transfection of either RXR or PPAR alone resulted in activation less than that observed when both expression vectors were introduced. The capacity of a single coregulator (RXR) to promote a discriminatory function in DNA site targeting suggested that binding site specificity is conferred both by RXR and the respective nuclear receptor partner. The activation of the ERE-dependent reporter gene by PPAR depends on the RXR as deletion of the DBD of RXR reduces the observed reporter activity. The finding of the experiment explained in the chapter that PPAR and RXR activate an estrogen-responsive element suggests that the two receptors are involved in a mechanism to generate diversity and tissue-specific regulation of estrogen-responsive genes. The concept that receptors other than the ER control estrogen responsive genes is supported by the presence of natural EREs such as in the rat oxytocin promoter, where the ER, TR, RAR and a COUP-like factor have been suggested to control expression of the gene.