Volume 14, Issue s2

Congenital adrenal hyperplasia (CAH) is a family of adrenal disorders whereby cortisol biosynthesis is impaired or abolished. In most cases, CAH is caused by a deficiency of the enzyme 21-hydroxylase causing a massive build up of adrenal precursors. In addition to prenatal virilisation of genetic females and postnatal virilisation of both males and females, short adult stature is characteristic of the disorder. The inadequate final height in CAH patients is often attributed to overtreatment with glucocorticoid replacement and poor control of adrenal androgen levels. In a recent study, the use of growth hormone alone and in combination with gonadotropin releasing hormone analogue in children with CAH and poor predicted final height was found to decrease height deficit after one and two years of treatment.

Short stature is present in a significant percentage of patients affected by β-thalassaemia major. Growth failure of patients with thalassaemia is multifactorial. The most important contribution is attributed to the toxic effect desferrioxamine and to endocrine disorders, due to iron overload. The commonest endocrine complication is hypogonadism. The growth pat- tern of patients with thalassaemia is characterized by normal growth during childhood, a deceleration of growth velocity around age 9-10 years, and a reduced pubertal growth spurt. In addition, reduced growth of the trunk is often present. Short stature and short trunk are more evident at pubertal age. Hypogonadism is usually considered responsible for the pubertal growth failure, as well as the aggravation of body disproportion at pubertal age. However, data suggest that pubertal height gain and final height are reduced in both patients with spontaneous puberty and patients with induced puberty. It is concluded that several aspects of peripubertal growth in patients with thalassaemia remain to be clarified.

Many children with chronic renal insufficiency (CRI) show growth retardation and severely delayed pubertal development. Successful renal transplantation (RTx) also rarely results in full growth rehabilitation. Pubertal height gain in CRI patients is only 58% and 48% of that observed in late-maturing boys and girls, respectively. Growth retardation in both CRI and RTx patients is not the result of abnormal GH secretion or decreased levels of IGF-I, but rather of elevated levels of IGFBPs inhibiting the bioavailability of the IGFs. In RTx patients prednisone may also inhibit growth directly via inhibition of bone matrix formation. Several studies have convincingly shown that GH therapy at a dose of 4 IU/m 2 /day results in a sustained improvement of growth in prepubertal and pubertal children with CRI and in growth-retarded prepubertal and pubertal post-transplant patients. The following consensus was reached concerning optimal therapy of puberty in children with chronic renal disease. GH therapy does not lead an earlier start of puberty. It is safe to give GH to RTx patients if transplant function is stable. GH therapy will not accelerate bone maturation and can improve the final height of children with CRI and after RTx. Increasing the GH dose above 4 IU/m 2 /day in pubertal RTx patients does not increase height gain or final height and is not advised as it may increase insulin resistance. GH should best be started before the start of the pubertal growth spurt but will still be effective, in RTx patients with advanced bone age. GH testing should not be a prerequisite for starting GH therapy. It is important to optimise other therapies during puberty. During GH therapy of RTx patients use minimum daily, not alternate-day, steroid dosing. Further research is still required on the possible long-term effects of GH therapy in children with chronic diseases. Two studies demonstrated improved long-term growth and final height within the target height range, without significant side effects. Renal graft function did not deteriorate more than in matched controls. A GH dose of 4 IU/m 2 /day proved adequate.

Constitutional delay of growth and puberty (CDGP) is the most common presenting form of short stature, but no single test can infallibly discriminate CDGP and isolated hypogonado- trophic hypogonadism. Management of puberty in CDGP aims to optimise not only growth - maintaining body proportions and improving peak bone mass without impairing growth potential - but also well-being; for example, the distress boys often suffer because of their lack of growth and pubertal progression can affect their school performance and social relationships. Typical sex steroid treatments to induce puberty in boys with CDGP include testosterone (T) enanthate, T undecanoate, mixed T esters, T transdermal patches, and oxandrolone p.o. Compared with other regimens, short-course low-dose depot T i.m. is an effective, practical, safe, well tolerated, and inexpensive regimen. Some unresolved problems in management include optimal timing and dose of sex steroid treatment, the role of GH in CDGP, and the management of CDGP in girls.

Turner syndrome (TS) is the most common sex-chromosome abnormality in females. Short stature and hypogonadism are the classical clinical findings. The spontaneous final height (FH) ranges between 139 and 147 cm, representing a growth deficit of about 20 cm with respect to the unaffected population. GH therapy improves FH and should be started during childhood at a high dose of about 1 IU/kg/week (range 0.6-2 IU/kg/week). Some authors advocate combined therapy with an anabolic steroid at various doses (e.g. oxandrolone 0.05-0.1 mg/kg/day). This treatment results in a significantly increased FH, .a large proportion of treated girls reaching a FH of more than 150 cm. Gonadal function is compromised during adolescence in about 80% of girls with TS, whilst in about 20% pubertal development occurs spontaneously. Oestrogen therapy should be started at the age of 13-14 years in hypogonadic patients; early onset of treatment (before 12 years) seems to compromise FH. Other concerns in these patients are fertility and osteopenia.

Idiopathic short stature (ISS) is a term used to describe the status of children with short stature that cannot be attributed to a specific cause. Many children diagnosed as having ISS have partial GH insensitivity, which can result from disturbances at various points of the GH-IGF-I axis. Several clinical studies on spontaneous growth in ISS showed that adult height was almost in the range of target height. GH treatment led to adult height not significantly higher than the pretreatment predicted adult height in most reports. No metabolic side effects have been observed, even when the dose was higher than in GH deficiency. Manipulation of puberty with gonadotrophin releasing hormone analogues reported by a few authors in a small number of children has shown conflicting results. Long-term psychological benefits of GH therapy for short normal children have not been demonstrated to date.

In this overview an update is given on the pathogenesis, classification and differential diagnosis of overgrowth syndromes. In addition, height prognosis and therapeutic modalities available for managing mainly constitutional tall stature are discussed. Constitutional tall stature comprises normal variants in which one or both parents are tall. Primary disorders may have a prenatal onset and may be of chromosomal or genetic origin. Secondary overgrowth syndromes are most often the result of hormonal disturbances. Height prediction plays a key role in the management of tall children. Prediction equation models have been developed based on the growth data of healthy tall children. There is general agreement that a favourable effect on reducing ultimate height is obtained using high doses of sex steroids (girls 100-300 μg ethinyl- oestradiol; boys testosterone (T) ester depot preparations 250-1000 mg/month), the height reduction being greater when the treatment is started at a lower chronological and/or bone age. An alternative is the induction of puberty with low doses of sex steroids (girls 5-50 μg ethinyloestradiol; boys T esters 25-50 mg/m 2 /3 wk). In addition orthopaedic procedures have been suggested, but there is limited experience. Although psychosocial factors constitute the main reason for treating tall stature, extensive psychological investigations before or during height limiting therapy are lacking. Moreover, there are no objective data indicating lifelong psychosocial damage resulting from being tall.

GnRHa have been used in the treatment of central precocious puberty (CPP) for a decade and some final results of this therapy are now available. Treatment preserves height potential in younger patients and a complete recovery of the hypothalamic-pituitary-gonadal axis occurs at the end of treatment. However, some aspects of the management of CPP are still debated. Probably the age limits between normal and precocious puberty have to be lowered, and new diagnostic tools will modify and simplify diagnostic criteria. The possibility of progression of premature thelarche into precocious puberty, the pathogenesis of organic and idiopathic precocious puberty, the criteria for decision to treat and to stop treatment and the utility of an association with GH treatment will be better understood in the future. Follow-up of patients after stopping therapy includes frequency and characteristics of menses, the possible higher incidence of polycystic ovary-like syndrome and the correct achievement of a normal peak bone mass and body composition. In this review we discuss some of these points, with particular attention to precocious puberty in girls.

Specialised clinics for the long-term follow-up of survivors from childhood cancer have developed over recent years. The problems encountered among patients who received multiple chemotherapy and radiotherapy can be challenging and require high expertise and close collaboration among different professionals (e.g. oncologists, endocrinologists, radiotherapists, psychologists). Endocrine disorders are often seen, particularly among those who received cranial radiotherapy or gonadotoxic chemotherapy; puberty can be affected and the spectrum of disorders may range from precocious or accelerated puberty to delayed, arrested or even absent pubertal development. Growth impairment can be multifactorial and growth hormone deficiency is an important but probably not the only factor involved. Many questions remain about the optimal management of this group of young patients. In the consensus guidelines that follow the overview an attempt is made to help optimise patients’ growth and puberty by suggesting practical clinical approaches to some of the most challenging issues.

Although it is difficult to reach international agreement on the definition of growth hormone deficiency (GHD) in children and adolescents, great efforts to do so have been made during the last two decades. A somewhat limited definition of GHD is: a combination of auxological, clinical, biochemical and metabolic abnormalities caused by lack or insufficiency of GH secretion that results in a decrease in the production of GH-dependent hormones and growth factors. Its aetiology is very complex. Therefore, specific studies must be performed during different periods of childhood (neonatal, prepubertal and pubertal periods). Auxological parameters, particularly growth velocity (GV), are still considered the best clinical measures for analysing human growth. The spectacular advances in our understanding of molecular biology during the past twenty years have allowed, and will continue to allow, a more and more precise diagnosis of the molecular anomalies of human growth. This will, in turn, allow changes caused by genetic lesions to be more efficiently distinguished from those due to nutritional, organic, tumoural, psychological or traumatic causes. Our knowledge of the molecular bases of undergrowth due to a deficiency in GH has developed as a result of the localisation and characterisation of human genes which code for proteins implicated in the hormonal regulation of growth. These genes include pituitary GH (GH1), pituitary transcription factor 1 (Pit-1), the prophet of Pit-1 (PROP-1), the pituitary; transcription factor LHX3, the transcription factor HESX1 and the GH-releasing hormone receptor (GHRHr). In addition, magnetic resonance imaging is the best available imaging method for the evaluation of size and structure of the pituitary and the parasellar region.

The overview in this paper focuses on ways of achieving optimal auxological results in puberty, principally in idiopathic and congenital multiple pituitary hormone deficiency (MPHD), suggested by the co-authors. We agreed that diagnosing gonadotrophin insufficiency/deficiency is difficult in young children and should be repeated in late prepuberty, but a firm diagnosis of MPHD helps avoid endocrine re-testing at the end of growth. The hypothalamic-pituitary axis must be reassessed periodically in evolving endocrinopathies, though current practice varies widely. Optimum age to induce puberty is 11-12 years in girls and 13-14 boys, and sex steroids are the preferred agents. Short-course testosterone to increase micropenis size is advantageous, but inducing early testicular maturation is not known to improve later fertility. There is also little evidence for increasing the dose of GH during puberty, though therapy should continue to final height, and possibly until peak bone mass is achieved. Delaying puberty is an option in septo-optic dysplasia, and minimising the dose of hydrocortisone is crucial in treating ACTH/ cortisol insufficiency. Many unresolved questions remain in this difficult area.