Endocrine sequelae of cancer therapy in childhood.

New treatments for neoplastic diseases of childhood have significantly increased patients' long-term survival and the importance of recognizing and correcting late complications of medical therapy. In this review, we examine both central nervous system (CNS) and non-CNS-related endocrine morbidities associated with chemotherapy and radiation therapy of childhood cancer. These include effects on growth, puberty, fertility, thyroid and adrenal function which may present many years after the successful treatment of underlying disease.

Is short stature a handicap? A comparison of the psychosocial functioning of referred and nonreferred children with normal short stature and children with normal stature.

OBJECTIVES: Normal short stature (NSS), defined as height below the 5th percentile for age and sex norms that is not due to illness, hormonal deficiency, or part of a dysmorphic syndrome, has been thought to have a deleterious effect on psychosocial functioning based on observations of referred populations. Recent studies of nonreferred children with NSS, however, have demonstrated normal function. This study directly compared the psychosocial functioning of referred children with NSS, nonreferred children with NSS, and children with normal stature. STUDY DESIGN: Participants, 90 children (46 boys, 44 girls) between 6 and 12 years of age (mean, 9. 6 years), were administered intelligence and achievement tests. Parents and teachers assessed adaptive and problem behaviors. Family adaptability and cohesiveness were measured. RESULTS: Intelligence and achievement for referred and nonreferred children with NSS were average. Referred children with NSS were reported to have more externalizing behavior problems and poorer social skills than nonreferred children with NSS and children in the control group. Family adaptability and cohesiveness were comparable across groups. CONCLUSIONS: Children with NSS have normal psychosocial function, and results suggest that externalizing behavior problems, attention problems, and poor social skills in children referred to clinics for NSS are inappropriately attributed to short stature.

A spun-column assay for determination of leptin binding in serum.

Serum collected from 27 patients was assayed simultaneously using a spun-column assay (SPC) and a traditional exclusion gel-filtration assay (GFC) to determine specific leptin binding. The levels of serum leptin binding determined by either assay correlated inversely with serum leptin levels (SPC, r = 0.63, P < 0.001; GFC, r = 0.79, P < 0.0001). Although specific leptin binding as determined by the traditional exclusion gel-filtration assay was generally higher than that obtained by the spun-column assay (mean = 18.3% vs 14.0%, P < 0. 02, respectively); the values obtained between the two assay methods were highly correlative (r = 0.89, P < 0.0001). By varying either the amount of 125I-leptin or the amount of competitor, analysis was carried out using the spun-column assay to determine the intrinsic properties of serum leptin binding. Results yielded a Kd = 0.3 nM, where each variable amount of leptin or competitor was carried out in duplicate. The complete analysis was carried out in the time that it typically takes for a single sample determination by the traditional exclusion gel-filtration assay. We conclude that the "spun-column" assay is a useful method for rapid and accurate quantification of leptin binding in serum.

t(1;18)(q32.1;q22.1) associated with genitourinary malformations.

We report a male infant who has impaired penile development, hypospadias, and mild developmental delay with a 46,XY,t(1;18)(q32.1;q22.1) karyotype. Fluorescent in situ hybridization (FISH) was performed to more precisely map the translocation breakpoint. The translocation breakpoint maps to a region that has been implicated in genitourinary malformations in the 18q- syndrome. This case report suggests that a gene involved in genitourinary development maps at or near the chromosome 18 translocation breakpoint.

Newer aspects of the pathophysiology, evaluation, and management of obesity in childhood.

Childhood obesity is a silent epidemic in America. Although most practicing pediatricians recognize clinically significant obesity and are aware of its potential morbidities, they often lack the tools to accurately quantify it, are rarely able to successfully treat it, and usually have no consistent approach to its prevention. In this update, recent information concerning the measurement, prevalence, natural history, complications, causes, evaluation, and management of childhood obesity is discussed.

The role of serial sampling in the diagnosis of growth hormone deficiency.

We analyzed 12-hour serial sampling of growth hormone (GH) levels in two cohorts of short children: 96 children referred to a university endocrine clinic or studied on a research protocol and 825 children in the National Cooperative Growth Study of children treated with exogenous GH. The mean 12-hour GH levels correlated with growth velocity in 60 children with normal height and growth velocity in the university study, and this correlation was stronger in the boys. The testosterone levels also correlated with growth velocity and mean 12-hour GH levels in the boys. The mean 12-hour GH levels were lower in a group of 36 children with idiopathic short stature than in the control subjects, as were the peak GH levels within 1 hour after the onset of sleep and the insulin-like growth factor I levels. In the National Cooperative Growth Study cohort, pooled 12-hour GH levels were lower in the group with idiopathic GH deficiency (n = 300) than in the group with idiopathic short stature (n = 525), but the difference was not significant. The duration of GH treatment was the most significant predictor of change in the height SD score in both groups. Indices of spontaneous secretion of GH were not predictive of the response to GH treatment, nor were the results of provocative GH testing, the responses to GH treatment being similar in both groups over time. We conclude that the results of GH testing must be interpreted for each patient and that several testing modalities may be helpful in finding GH insufficiency that originates at various levels of the somatotropic axis.

Atypical dendritic cell-related histiocytosis with goiter and primary hypothyroidism.

Langerhans cell histiocytosis may be seen with goiter and histiocytic infiltration of the thyroid. We report a 2 1/2-year-old boy who had goiter and primary hypothyroidism develop, later had pulmonary disease, and died of neurologic involvement. Autopsy lesions suggested a transitional dendritic cell precursor of the epidermal Langerhans cell. Of the reported cases of Langerhans cell histiocytosis with goiter in children and adolescents, 82% were male when the relative incidence of Langerhans cell histiocytosis is two males to one female.

Demonstration of a leptin binding factor in human serum.

Serum leptin levels are elevated in subjects with exogenous obesity, indicating that obesity is associated with leptin resistance. Since in man no abnormalities have yet been found in either the genes for leptin or its receptor, the mechanism of leptin resistance in obesity remains unknown. To determine if resistance might be related to leptin binding by a serum component, we assessed the carrier status of leptin in serum. The presence of a specific leptin binding factor in human serum has been established by (1) demonstrating [125I]-leptin binding to a serum component that is saturable and specifically displaceable only by unlabeled leptin and not by human growth hormone, pork insulin, insulin-like growth factors I and II, luteinizing or follicle stimulating hormones, transforming growth factor-beta 1, interleukin-6, or leukemia inhibiting factor; (2) fractionating the leptin bound serum complex and the serum leptin binding component on a molecular sieving column revealing a mass of approximately 450 kDa; and (3) identifying an inverse correlation between the concentration of serum leptin and the quantity of the leptin binding component. It is suggested that binding of leptin by this serum component may influence the physiologic response to leptin.

Autoimmune hyperthyroidism in prepubertal children and adolescents: comparison of clinical and biochemical features at diagnosis and responses to medical therapy.

We explored our clinical impression that young children with autoimmune hyperthyroidism are more thyrotoxic at presentation and require a longer course of medical therapy than do adolescents to achieve remission. A retrospective chart review of clinical and biochemical data at presentation and response to therapy in 32 prepubertal (PREPUB) and 68 pubertal (PUB) children and adolescents with autoimmune hyperthyroidism was undertaken. Initial therapy included prophylthiouracil or methimazole in all but 11 patients who chose radioactive iodine (131I); 30 additional patients ultimately chose 131I or surgery after an initial period of medical therapy. In PREPUB children there were significantly longer duration of symptoms (7.8+/-7.7 months) and higher serum concentrations of triiodothyronine (T3) 708+/-330 ng/dL) at presentation than in the PUB group (4.7+/-3.4 months; p < .05) (537+/-197 ng/dL; p < .01). Duration of symptoms correlated negatively with chronologic age (r = -0.24; p < .02) but not with T3 or thyroxine (T4) levels (p = .1). PUB children had significantly higher titers of thyroid microsomal antibodies (positive dilution factor 1:6022+/-14572) than did PREPUB children (1:592+/-1226; p < .05). There was a higher familial incidence of thyroid disease in boys (80%) than in girls (64%) (p < .02). The duration of medical therapy was significantly longer (3.5+/-2.9 years) in PREPUB children compared to the PUB group (2.2+/-1.8 years) (p < .05). Only 17% of PREPUB treated 5.9+/-2.8 years compared with 30% of PUB treated 2.8+/-1.1 years achieved a 1-year remission after stopping antithyroid medication (percentage between groups, p < .01; years of treatment, p < .05). The median time to remission after medical therapy was 8 years in PREPUB and 4 years in PUB (p < .02). PREPUB children continued to remit after prolonged medical therapy (>6 years) whereas PUB patients did not. Total treatment length correlated negatively with chronological age (r = -0.26; p < .05) and positively with T4 and T3 concentrations at diagnosis (r = 0.31; p < .01). The diagnosis of hyperthyroidism is delayed in prepubertal children compared to adolescents. This delay may contribute to the higher T3 levels observed in this group at presentation. Prepubertal children also appear to require longer medical therapy to achieve a lower rate of remission, but do continue to remit after prolonged treatment. These differences in response to therapy should be considered when discussing therapeutic options with the family.

Heterogeneity of activating mutations of the human luteinizing hormone receptor in male-limited precocious puberty.

Male-limited precocious puberty (MPP) is a gonadotropin-independent disorder that occurs sporadically or is inherited in an autosomal dominant, male-limited pattern. Recent studies have identified constitutively activating missense mutations in the human luteinizing hormone receptor (hLHR) gene leading to Leydig cell activation and precocious puberty. Patients with sporadic MPP (SMPP) or with different ethnic backgrounds appear to have a greater likelihood of having novel mutations. In the current study we examined genomic DNA from two unrelated cases of SMPP of African-American descent for novel mutations of the hLHR gene. A heterozygous A to C transversion at nucleotide 1723 resulting in substitution of Leu for lle575 in transmembrane helix 6 was identified. Human embryonic kidney cells transfected with cDNA for the mutant hLHR-I575L, created by polymerase chain reaction-based mutagenesis of the wild-type (hLHR-wt) cDNA, exhibited increased basal levels of cAMP production in the absence of agonist, indicating constitutive activation. Surface expression of hLHR-I575L, as reflected by human chorionic gonadotropin binding, was diminished compared to hLHR-wt, while agonist affinity was unaffected. With the exception of two polymorphic bases, no mutation was identified within the coding sequence of the hLHR in the second case of SMPP. We conclude that I575L is a unique constitutively activating mutation that impairs cell surface expression of the receptor but does not alter agonist affinity. Furthermore, mutations of the hLHR gene causing SMPP are highly heterogeneous and may be found in regions other than exon 11 of the hLHR. Last, patients with MPP from different ethnic backgrounds are likely to have novel mutations.

Hetero- and isosexual pseudoprecocity associated with testicular sex-cord tumors in an 8 year-old male.

Enlargement of the right breast, axillary hair, and acceleration of linear growth rate were first noted at 8 years of age in an otherwise healthy male with no known exposure to exogenous hormones. At 9.5 years of age the right subareolar mass was excised; histologic examination revealed fibrous breast tissue. Subsequently pubic hair appeared. At 10.7 years of age, the patient complained of right inguinal pain after a minor injury. Examination revealed a tall (height age 12.7 years), mature, muscular boy with enlarged (R: 5 x 3 x 2 cm; L: 3 x 2 x 3 cm) firm, irregular testes, Tanner stage II pubic hair, and modest axillary hair. No perioral pigmentation was present. Testicular ultrasonography revealed multilobular echogenic foci with calcifications. Bone age was 13 years, the LH and FSH secretory responses to GnRH were minimal (LH: < 0.038-->0.28 mIU/ml; FSH: < 0.063-->0.11 mIU/ml), and basal serum testosterone (< 10 ng/dl) and estradiol (< 10 pg/ml) values were undetectable. Following administration of human chorionic gonadotropin (hCG), the serum testosterone concentration increased to 275 ng/dl, while estradiol remained unmeasurable. Spermatic vein concentrations of testosterone were undetectable in the basal state and increased after hCG administration. After bilateral orchiectomy, pathologic examination revealed multifocal tumors composed of brightly eosinophilic, large polygonal cells arranged in nests, cords, and clusters within dense connective tissue or mucinous stroma with lamellar calcifications of varying sizes. These pathologic findings were compatible with a large cell calcifying Sertoli cell (sex-cord)tumor of the testes. Testosterone, estradiol, immunoreactive and bioactive aromatase activity were not detectable in the tumor. Thus, both heterosexual (gynecomastia) and isosexual (increased musculature, pubic and axillary hair) precocious puberty may occur in boys with testicular sex-cord tumors.

A randomized, double blind, placebo-controlled trial on safety and efficacy of recombinant human insulin-like growth factor-I in children with growth hormone receptor deficiency.

GH insensitivity due to GH receptor deficiency is a rare autosomal recessive condition, characterized by deletions or mutations of the GH receptor gene. Patients are refractory to both endogenous and exogenous GH, resulting in severe growth retardation. Therapy with recombinant human insulin-like growth factor-I (rhIGF-I) can bypass the defect in the GH receptor and potentially stimulate growth. We previously identified a genetically homogeneous group of patients in southern Ecuador, thus providing a patient base for a controlled clinical trial of rhIGF-I therapy. Seventeen prepubertal patients were entered in a randomized, double blind, placebo-controlled trial. Subjects received either a 12-month course of rhIGF-I (120 micrograms/kg, sc, daily) or 6 months of placebo followed by 6 months of rhIGF-I. Subjects receiving rhIGF-I showed a significant increase in growth rate, which was sustained over the 1-yr course of therapy (from 2.9 +/- 0.6 to 8.6 +/- 0.4 cm/yr). Incidents of hypoglycemia were equal in frequency in the placebo and rhIGF-I groups. One recipient of rhIGF-I developed papilledema, which resolved spontaneously. rhIGF-I therapy did not alter serum IGF-binding protein-3 concentrations. rhIGF-I treatment is effective in stimulating skeletal growth in GH receptor deficiency. Although the therapy proved to be safe, the potent metabolic actions of rhIGF-I and the persistently low levels of serum IGF carrier protein necessitate continued careful observation for side-effects.

Primary care for women. Comprehensive assessment of the respiratory system.

This article reviews the anatomy and physiology of the respiratory system and provides techniques for the physical assessment and data collection for common respiratory complaints in women. The pertinent historical, physical examination, and laboratory data for asthma, pneumonia, bronchitis, cough, and tuberculosis are also presented. This article is the first of two articles on primary care for women with respiratory complaints; the subsequent article will address primary care management of common respiratory conditions.

Effects of insulin-like growth factor I treatment on the molecular distribution of insulin-like growth factors among different binding proteins.

The molecular distribution of insulin-like growth factor I (IGF-I) and IGF-II among the IGF binding proteins (IGFBPs) was studied before and during IGF-I therapy in Ecuadorean adults with growth hormone receptor deficiency (GHRD). Of the total circulating IGF-I and IGF-II, 70% was carried by the 150 kDa complex in normal subjects, while in patients with GHRD, 50% of serum IGF-I, but only 30-35% of serum IGF-II, was measured within the 150 kDa IGFBP-3 region. Administration of IGF-I altered the concentration of IGF-I and IGF-II, although the percentage of total IGF measured within each IGFBP region was not affected, as the increase in IGF-I and the decrease in IGF-II were proportional. Similarly, serum concentrations of IGFBP-3 and the acid-labile subunit, measured by radioimmunoassay, were unaltered. Thus, administration of IGF-I to patients with GHRD was unable to correct the aberrant distribution of IGFs among the IGFBPs.

Body changes in adolescent patients with growth hormone receptor deficiency receiving recombinant human insulin-like growth factor I and luteinizing hormone-releasing hormone analogue: preliminary results.

Auxological and body composition changes were studied in three adolescent patients (2 female, 1 male) with growth hormone receptor deficiency (GHRD) given insulin-like growth factor I (IGF-I), 120 micrograms/kg s.c. twice daily, plus a monthly intramuscular injection of 7.5 mg of a luteinizing hormone-releasing hormone (LHRH) analogue. Preliminary results from the first 12 months of the study show that height velocity was increased compared with the pretreatment values. This increase was probably due to the IGF-I therapy, as the LHRH analogue would have suppressed gonadotrophins and gonadal steroid production. There was a reduction in percentage body fat, and increases in lean mass and the lean:fat ratio, whole body mineral content and body calcium content, even when expressed per kg body weight. There was also a trend towards increased bone mineral density of the whole skeleton, lumbar spine and femoral structures, as well as a maturation of facial features. These preliminary results indicate that concomitant therapy with IGF-I and an LHRH analogue is safe and efficacious in inducing growth without advancing bone age in patients with GHRD.

Heart rate increases in patients with growth hormone receptor deficiency treated with insulin-like growth factor I.

Cardiac function was measured in 16 prepubertal Ecuadorean patients with growth hormone receptor deficiency given insulin-like growth factor I (IGF-I) during part of a clinical trial. The IGF-I was given subcutaneously twice daily at a dose of 40 micrograms/kg on days 1 and 2, 80 micrograms/kg on days 3 and 4, and 120 micrograms/kg thereafter. Heart rate was determined at baseline (pretreatment) and on days 1-7 by repeated palpation of the radial artery and at baseline and on days 2, 4 and 7 by continuous portable Holter monitoring. Heart rate measured by both methods rose progressively with increasing doses of IGF-I. The mean palpated pulse exceeded baseline on each treatment day and was significantly higher on day 5 than day 4 and significantly higher on day 3 than day 2. The mean Holter heart rate was significantly higher on day 4 than on day 2 and significantly higher on day 2 than at baseline. Non-significant glucose and electrolyte changes did not appear to be associated with the cardiac events.