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.

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 more than the mean, which corresponds to an age of approximately 14 years for boys and 13 years for girls. The actual incidence of pubertal delay associated with chronic illness is unknown. Delay is often considered to be acceptable as a consequence of the underlying disease and can be overlooked with other complications of the illness. However, because a larger proportion of patients with chronic disease are surviving longer and beyond the age of normal puberty, correct management of significant delay is increasingly important. Failure to do so may have a detrimental effect on final height, total bone mass and psychological health of the patients.

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 EB have abnormal growth and pubertal delay; the possible pathophysiology is discussed.

Regulation of growth and pubertal development

The hypothalamo-pituitary-gonadal axis is driven by intermittent discharges of gonadotrophin-releasing hormone (GnRH) generated by hypothalamic neurons known as the GnRH pulse generator. At puberty, increasing levels of GnRH and increased pituitary sensitivity to GnRH result in an increase in luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn stimulates ovarian/testicular activity and is directly responsible for most of the changes seen during puberty.

Leptin, a protein produced by adipocytes, has been proposed as the hormone responsible for the initiation and progression of puberty. Mice and rats deficient in leptin fail to undergo puberty, illustrating the importance of its role in rodents.

The integrity of the growth hormone (GH) insulinlike growth factor-1 (IGF-1) axis is critical for regulating growth during childhood and adolescence. GH is secreted in a pulsatile manner by the pituitary gland and binds to the GH receptor in the liver to generate IGF-1. The latter circulates bound predominately to IGF-binding protein-3 (IGF-BP3), which controls the availability of IGF-1 at tissue level. GH also acts directly on growth plates with amplification of local IGF-1 production.

A family of intracellular proteins known as suppressor of cytokine-inducible signaling (SOCS) are synthesized in response to inflammatory stimuli. They are physiological regulators of cytokine responses, including those that regulate the inflammatory systems. GH and leptin are inhibited by SOCS-2 and SOCS-3, respectively. Although at present the role of SOCS proteins in EB is unclear, in such an inflammatory disease it is likely to be important.

Causes of pubertal and growth delay in patients with EB

Malnutrition is a well-known cause of pubertal delay and this can affect the entire hormonal system (insulin, thyroid hormones, cortisol and GH, and the hypothalamo-pituitary-gonadal axis). The initial process seems to be hypoinsulinemia and an increase in GH secretion, which stimulate lipolysis to provide an alternative energy source. Subsequently modification of the hypothalamic secretion of growth hormone-releasing hormone (GHRH) occurs, resulting in increased serum levels of GH in conjunction with decreased levels of IGF-1 leading to a state of GH resistance and a reduction in growth velocity and skeletal growth. Malnutrition also affects the maturation of the hypothalamo-pituitary-gonadal axis causing delay in the pulsatile secretion of GnRH, the onset of puberty and consequent growth spurt. Patients with severe types of EB and pubertal delay at Great Ormond Street Hospital in London have been found to have hypogonadotrophic hypogonadism; that is, secondary hypogonadism with reduced/low normal serum LH and FSH concentrations (A. Martinez and C. Brain, personal communication, 2010). Although the hormonal system has been poorly evaluated in patients with EB to date, malnutrition or nutritional compromise is likely to play one of the principal roles in delayed growth and puberty in this cohort of patients.

An imbalance of proinflammatory cytokines, notably interleukin-1B (IL-1B), tumor necrosis factor (TNF) and interleukin-6 (IL-6), is seen in children with inflammatory diseases. Studies have shown that IL-6 and IL-1 can inhibit steroidogenesis in the ovary and the testis and inhibit secretion of GnRH by direct action on the hypothalamus. In addition, IL-6 inhibits hepatic GH signaling by inducing SOCS-3, as well as increasing proteolysis of IGFBP-3 with impaired formation of the IGF-1/IGFBP-3/acid labile subunit complex, resulting in a shorter half-life and enhanced clearance of IGF-1. TNF-alpha also lowers IGF-1 by reducing hepatocyte expression of the GH receptors. Although there are no data published on the GH/IGF-1 axis in EB patients, measurement of serum concentrations of IGF-1 and IGF-BP3 have been found to be greatly reduced in children with severe generalized recessive dystrophic EB in a London center (Anna Martinez, personal communication, 2010), supporting the possible effects of the inflammatory cytokines. The combination of nutritional compromise and a chronic inflammatory state are likely therefore to result in abnormalities in the GH/IGF-1 axis with partial GH resistance and effects on the function of the hypothalamo-pituitary-gonadal axis with hypogonadotrophic hypogonadism.

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