Growth and the Growth Hormone-Insulin Like Growth Factor 1 Axis in Children With Chronic Inflammation: Current Evidence, Gaps in Knowledge, and Future Directions.

Growth failure is frequently encountered in children with chronic inflammatory conditions like juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis. Delayed puberty and attenuated pubertal growth spurt are often seen during adolescence. The underlying inflammatory state mediated by proinflammatory cytokines, prolonged use of glucocorticoid, and suboptimal nutrition contribute to growth failure and pubertal abnormalities. These factors can impair growth by their effects on the GH-IGF axis and also directly at the level of the growth plate via alterations in chondrogenesis and local growth factor signaling. Recent studies on the impact of cytokines and glucocorticoid on the growth plate further advanced our understanding of growth failure in chronic disease and provided a biological rationale of growth promotion. Targeting cytokines using biological therapy may lead to improvement of growth in some of these children, but approximately one-third continue to grow slowly. There is increasing evidence that the use of relatively high-dose recombinant human GH may lead to partial catch-up growth in chronic inflammatory conditions, although long-term follow-up data are currently limited. In this review, we comprehensively review the growth abnormalities in children with juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis, systemic abnormalities of the GH-IGF axis, and growth plate perturbations. We also systematically reviewed all the current published studies of recombinant human GH in these conditions and discussed the role of recombinant human IGF-1.

Growth problems in children with IBD.

Crohn's disease in childhood causes linear growth retardation, which has a substantial effect on management of this disease. By contrast, growth is rarely a problem in children presenting with ulcerative colitis. Depending on how growth failure is defined, approximately one-third of children with Crohn's disease have growth retardation at diagnosis. Although corticosteroids can suppress growth, decreased height at diagnosis demonstrates that this finding is a consequence of the disease and not merely an adverse effect of treatment. Both inflammation and undernutrition contribute to decreased height velocity. Increased cytokine production acts both on the hepatic expression of insulin-like growth factor 1 (IGF-1) and at chondrocytes of the growth plates of long bones. Growth hormone insensitivity caused by deranged immune function is a major mechanism in growth retardation. Resolution of inflammation is the cornerstone of treatment, but current studies on growth hormone and IGF-1 might yield therapies for those children whose inflammation is refractory to treatment.

Growth and pubertal delay in patients with epidermolysis bullosa.

Puberty is the acquisition of secondary sexual characteristics, associated with a growth spurt, resulting in the attainment of reproductive function and final adult height. Delayed puberty is defined as the absence of any pubertal development at an age 2 standard deviations (SD) more than the mean, which corresponds to an age of approximately 14 years for boys and 13 years for girls. The degree to which growth and pubertal development are affected in chronic illness depends on the disease itself, as well as factors such as age of onset, duration and severity; the earlier the onset and the more severe the disease, the greater the effect on growth and pubertal development. Most children with severe types of epidermolysis bullosa have abnormal growth and pubertal delay. The possible pathophysiology is discussed.

[Immunogenetic characteristics of nuclear families of adolescents with delayed sexual development]. / Immunogeneticheskaia kharakteristika iadernykh semei podrostkov s zadezhkoi polovogo razvitiia.

The paper submits data on the antigenic composition of HLA system in members of nuclear families of adolescent boys presenting with the delay in sexual maturation. Positive and negative associations of particular antigens with sexual underdevelopment are stated. Estimated in the families was the highest incidence rate of gaplotypes A 28-B 40, A 28-B 8, A 1-B 40, and A 3-B 40. The authors come out with a suggestion that it might be possible to use the identified antigens in prognostication of delayed puberty.

[The HLA system antigens in delayed sexual development]. / Antigeny sistemy HLA pri zaderzhke polovogo razvitiia.

Frequency distribution of HLA antigens of A and B loci was examined in 138 adolescent boys aged 14-18 with delayed sexual development (DSD) of stages I-III, residing in the north-eastern region of Ukraine. Increase of A28- and B40-antigens and haplotypes A1-B40, A28-B40, A10-B40 determination frequencies was established. There were revealed positive and negative correlation between some of HLA antigens and DSD. Relative and attributive risks of DSD formation were calculated.

A comparison of IGF-I levels measured by two commercially available radioimmunoassays.

Insulin-like growth factor I levels were measured in a parallel fashion in 77 extracted sera using the INCSTAR RIA (radioimmunoassay) and in the EDTA plasma of the same subjects by the NICHOLS RIA. The subjects suffered from untreated hGH deficiency, short stature, delayed and precocious puberty and acromegaly. Significant differences (P less than 0.05) were found between the mean IGF-I levels of all groups using both RIA systems. However, using the INCSTAR RIA, 85% of IGF-I values in untreated hGH deficiency were below normal, and a rise in IGF-I detected in the sera of all 5 patients who were treated with hGH. Using NICHOLS RIA, 55% of basal IGF-I values were below normal and a hGH-stimulated rise in IGF-I was found in only two of the treated patients. The INCSTAR RIA seems more precise and reproducible than the NICHOLS RIA and enables better discrimination of hGH-deficient patients from age-matched controls.

Urticaria associated with antigonadotropin-releasing hormone antibody in a female Kallman's syndrome patient being treated with long-term pulsatile gonadotropin-releasing hormone.

The administration of pulsatile gonadotropin-releasing hormone (GnRH) has received increasing attention as a method of inducing ovulation or initiating puberty. Few side effects have been reported, although urticarial allergic reactions have been reported in the male. An 18-year-old female with hypogonadotropic hypogonadism and anosmia due to lack of endogenous GnRH was treated for 230 days using subcutaneous GnRH in an attempt to induce physiologic puberty. Just before anticipated menarche, therapy was discontinued because of the appearance of an urticarial reaction at the injection site as well as at previous injection sites. The presence of immunoglobulin G (IgG) antibodies against GnRH were subsequently identified in the patient's serum. These results further confirm the potential for antibody production to this small natural peptide in the female not previously exposed to GnRH. Some practical considerations for this form of therapy are highlighted.