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Growth is considered as one of the best indicators of a child's health and deviations from the normal range both for height and for rate of growth may indicate an underlying problem (1). The disorders of growth hormone (GH) in childhood comprise a spectrum of clinical conditions characterised by short stature of varying degrees of severity and slow growth caused by either abnormalities in GH itself, the GH-releasing hormone receptor (GHRHR) and the GH receptor (GHR). Abnormalities in GH itself include alterations in the production, regulation, secretion or bioactivity of GH and will be described in this chapter under GH deficiency (GHD). Abnormalities in the GHR may be due to genetic or acquired defects that cause a state of GH resistance or insensitivity and such conditions will be referred in this chapter as GH insensitivity syndromes (GHIS) (2).

The mature pituitary gland contains a functionally diverse population of specialised cell types that produce six hormones: GH, luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), prolactin (Prl) and adrenocorticotropin (ACTH). This differentiated structure is the result of a complex process that involves activation and repression of numerous genes encoding homeodomain transcription factors (3).

GH is a small protein hormone of 191 amino acids that causes growth of almost all tissues of the body by increasing cell number and cell size and by promoting differentiation of specific cells i.e., muscle cells. GH is secreted in a pulsatile fashion and is under the regulation of the hypothalamic hormones GHRH and somatostatin, (review in Chapter 1). In plasma the majority of GH circulates in the free form but ~40% of GH circulates bound to GH binding protein (GHBP) which in man corresponds to the extracellular domain of the GHR (4). GH signalling requires dimerisation of two GHR molecules to exert its full biological action (5). It is well established that one of the most important biological actions of GH is to induce the synthesis of insulin-like growth factor (IGF)-I in the liver and in other extra-hepatic tissues. Most of the circulating IGF-I is derived primarily from hepatic production (6), and it is believed that one of the main functions of circulating IGF-I is to mediate GH negative feedback (7).

The IGF system is composed of IGF-I and IGF-II, a family of six distinct IGF-binding proteins (IGFBP), acid labile subunit (ALS), specific IGF receptors and IGFBP proteases (6). IGF-I, IGFBP-3, IGFBP-5 and ALS are all GH-dependent proteins and reflect integrated GH secretion in post-natal life (6). Most of the IGF-I circulates bound to IGFBP-3 and to ALS, forming the 150-kDa ternary complex and IGF-I bound to these two proteins has a significantly extended half-life (8). It is worth noting that IGF-I is regulated by a number of other factors besides GH. Under physiological conditions circulating IGF-I, IGFBP-3 and ALS concentrations depend on age, gender and nutritional status (6).

The aim of this chapter is to briefly examine the different pathogenesis, clinical presentations, current investigations and treatment of GHD and GHIS in childhood and present the recent biochemical and molecular developments that have led to increasing understanding of the underlying defects in the GH axis

GROWTH HORMONE DEFICIENCY (GHD)

Pathogenesis

The alterations in the synthesis, secretion and bioactivity of GH are usually sporadic, heterogeneous and include genetic disorders some with well-established molecular defects. The heterogeneity exists in part due to the variety of causes of GHD, summarised in Table 1 (9).

However, the cause in the majority of GHD patients still is considered as idiopathic in nature. Idiopathic GHD may be defined as conditions in which no organic lesion can be identified during life. Defective synthesis or release of hypothalamic GHRH has been known to be the cause of GH deficiency in the majority of patients (10). Retrospective studies have shown a high incidence of perinatal problems such a breech births or vaginal bleeding in previously thought idiopathic GHD patients.

In recent years, spontaneous and experimental models of hypopituitarism have led to the identification and characterisation of novel genes encoding transcription factors necessary for pituitary development (11). Indeed a number of molecular abnormalities in the transcription factors have been identified causing different forms of congenital anterior pituitary hormone deficiencies (11). For example mutations in the gene encoding the Pit-1 transcription factor interfere with the embryological determination and ultimate functions of the anterior pituitary cells that produce GH, Prl and TSH and patients will present with combined pituitary hormone deficiency (12). Other causes of GHD in children are secondary to malformations, trauma, and infections of the central nervous system (CNS) or due to tumours in the hypothalamic-pituitary region.

The true incidence of GHD has not been established with certainty and its prevalence has been reported to be approximately of 1:3500 children.

Clinical presentations

Idiopathic hypopituitarism can present as an isolated hormone deficiency or be part of a combined pituitary hormone deficiency syndrome. In the neonatal period infants usually present with normal birth weight and birth length but impairment of linear growth will occur in the first two years of life. In the neonatal period, episodes of recurrent hypoglycaemia, prolonged jaundice or micropenis should alert the physician of the possibility of congenital hypopituitarism (13,14).

GHD can present as an isolated pituitary deficiency or can be associated with other pituitary hormone deficiencies, been the most common being TSH deficiency and less common gonadotrophin or ACTH deficiencies. Mineralocorticoid deficiency is rare in children with hypopituitarism since aldosterone secretion is largely independent of pituitary ACTH stimulation.

During early childhood isolated GHD can present with a classical phenotype of growth failure, protrusion of the frontal bones and poor development of the bridge of the nose. Closure of the anterior fontanel may be delayed and dental eruption and skeletal maturation are usually quite delayed. The penis is often small and this may be accentuated by the presence of truncal obesity. Delay of puberty is frequent. However if gonadotrophin function is intact, puberty will develop.

Genetic disorders of pituitary development

A great deal has been learned about the genetic causes of hypopituitarism over the past two decades (11). Many families have been described with isolated GHD, others with multiple pituitary deficiencies (12, 15-17). In addition, small and large pedigrees of resistance to the action of GH have been described in highly consanguineous communities (18-20).

The development of new molecular approaches allowed the identification of many genes that encode critical components of the hypothalamic pituitary axis. Data from studies of the "Little" mouse provided a model of isolated GHD, whereas Snell and Ames mice with small pituitary glands reflecting absence of somatotropes, lactotropes and thyrotropes, provided models of recessive multiple pituitary hormone deficiencies (11). The discovery of transcriptional activation factors that direct the embryonic development of the anterior pituitary in the late 1980's provided the clues to the understanding of the genes involved in pituitary development (11).

A brief description of the main transcription factors that have been implicated as causes of multiple pituitary hormone deficiency in humans follows.

Transcription factors of the anterior pituitary and combined hypopituitarism

Abnormalities of the transcription factor Pit-1 and of the Prop-1 gene are responsible for combined deficiencies affecting thyrotroph, somatotroph and lactotroph lineage's both in dwarf model strains (21) (Snell, Jackson and Ames) and in human patients. The chromosomal localisation of the human homologue genes is described in Table 2. More recently, gene knockout experiments have demonstrated the importance of other transcription factors such as Lhx3 and Lhx4 (22, 23) and HESX1 (24) in the development of the normal anterior pituitary gland.

Structural alterations of the GH molecule (Defects of the GH gene)

Deletions or gene defects of the GH-1 gene appear to result in four variants of hereditary GH (hGH) deficiency. Approximately, 3-30% of patients with isolated GHD had been reported to have an affected parent, sibling or child (25-28). Familial isolated GHD is associated with at least four Mendelian disorders. These include two forms that have autosomal recessive inheritance as well as autosomal dominant and X-linked forms as described below:

Type IA (recessive, absent GH, antibodies to hGH therapy; severe clinical phenotype)

Type IB (recessive, low GH, response to hGH therapy; clinical features include height SDS - 2)

Type II (dominant, low GH, response to hGH therapy; patients diagnosed with Type II have one affected parent and vary in clinical severity between kindreds).

Type III (X-linked, low GH, response to hGH therapy; Clinical findings differ in different families. Affected individuals have agammaglobulinemia associated with their IGHD but others do not).

The most severe form of isolated GHD is Type IA. Initially, all individuals with Type IA were found to be homozygous for GH1 gene deletions and they developed anti-GH antibodies with treatment. However, additional cases with complete GHD owing to GH1 gene deletions have been described who respond well to GH treatment. Therefore, the clinical response of patients with the same molecular defect varies and the presence of anti-GH antibodies is not universally found in this group of patients (28).

At the molecular level, Southern blot analysis showed deletions of approximately 6.7, 7.0 and 7.6 kb with a great majority being 6.7kb. GH1 gene deletions are now detected by polymerase chain reaction (PCR) amplification of the homologous regions flanking the GH1 gene and the fusion fragments associated with GH1 gene deletions (28).

Bioinactive GH syndrome

Severe short stature with low concentrations of IGF-I and normal to high GH concentrations suggest impaired GH effects as will be described below. Besides defects in the GH receptor, another possible cause to explain such findings is a biologically inactive GH molecule. Takahashi et al reported two point mutations in the GH1 gene (29), in which the mutant GH had impaired dimerisation with the GHR with subsequent impaired signal transduction. This was the first report demonstrating the molecular mechanism of bioinactive GH syndrome. A recent study investigated children with a similar phenotype showed a low GH response using an in vitro GH bioassay. However no mutations in the GH1 gene were found (30). These results suggest that mutations of the GH1 gene are rare causes of children with bioinactive GH syndrome.

Alterations in the GHRH receptor

GHRH receptor mutations have now been described primarily in isolated communities with high incidence of consanguinity. Small kindred's with severe familial isolated GHD due to mutations in the GHRHR were identified in the Indian subcontinent (31, 32). Recently, the largest kindred with a different molecular defect, a novel donor splice mutation in the GHRHR, was identified in Northeast Brazil (33).

Congenital structural CNS defects

Hypopituitarism as well as anomalous presentation of the pituitary or the pituitary stalk can result from a congenital mid-line malformation. Based on MRI studies these malformations have been divided into hypoplasia or aplasia, ectopic localisation and agenesia or pituitary stalk-section (34). These patients will present in addition to the presence of midline defects with symptoms and signs such as those described for congenital hypopituitarism.

Septo-optic dysplasia (De Morsier Syndrome), the combination of optic nerve defects and agenesia of the septum pellucidum, has been known for more than 50 years (35) and it is known that these abnormalities are associated with hypopituitarism. Dattani et al have shown that familial septo-optic dysplasia is associated with homozygosity for an inactivating mutation in the homeobox gene HESX1/Hesx1 in man and mouse (24). However, most septo-optic dysplasia occurs sporadically and recent studies of patients with mild forms of pituitary hypoplasia have shown a genetic basis, resulting from a heterozygous mutation of the HESX1 gene (36).

Acquired

Perinatal pathology (prenatal infections, trauma)

GHD associated with congenital rubella, toxoplasmosis and cytomegalovirus infections have been described (37). Perinatal trauma, especially associated with forceps delivery, vaginal bleeding and breech presentations (38).

CNS Tumours

Craniopharyngioma

Craniopharyngioma is the most common tumour in the hypothalamo-pituitary region to cause pituitary deficiency in childhood (39, 40). The tumour usually arises from remnants of Rathke's pouch, an invagination of the epithelium within the third pharyngeal pouch from which the anterior pituitary evolves. Although histologically a benign tumour, it is locally invasive, involving adjacent structures especially the optic tracts and base of the third ventricle. It usually has a solid and cystic component that may contain a cholesterol-rich fluid. The clinical presentation is usually characterised with signs and symptoms of increased intracranial pressure and visual disturbances due to the proximity of the optic chiasm. Visual field defects are common and include homonymous hemianopia, bitemporal hemianopia, decreased visual acuity and optic atrophy. GH deficiency (72%) is the most common endocrine abnormality at clinical presentation, followed by short-stature in 53% whereas ACTH, TSH and ADH deficiencies were found in approximately 25% of cases (39). The management of craniopharyngioma is complex, still controversial, and morbidity remains high. The choice of treatment varies from centre to centre including surgery with total removal; surgery with partial removal; irradiation; installation of radioactive substances to the cystic component or a combination of these treatment modalities. Following surgery endocrine deficiencies of ADH, ACTH, TSH, GH, LH and FSH are highly likely, therefore these patients should be carefully monitored and appropriate hormonal replacement therapies commence promptly. It is important to mention that many children who have been surgically treated for craniopharyngioma may continue to grow with a normal growth velocity despite having clearly documented low GH and low IGF-I. Hyperinsulinism associated with hyperphagia and the marked weight gain observed in these children may explain their normal growth velocity (41).

Germinomas and optic nerve gliomas: These tumours usually involve the hypothalamic-pituitary axis. Gliomas or astrocytomas usually present with increased intracranial pressure whereas germinomas may present with anorexia and weight loss in older boys and with diabetes insipidus alone. This latter condition may precede, sometimes for many years, the detection of the tumour itself by imaging studies and the clinical and biochemical evidence of other pituitary deficiencies (42). Therefore, idiopathic diabetes insipidus must always be investigated with regular CNS imaging. Pituitary stalk thickening may be the first radiological abnormality (43). Elevation of serum and possibly cerebrospinal fluid beta-human chorionic gonadotrophin (hCG) levels can be used as a tumour marker.

Optic nerve glioma, which occurs more commonly in patients with neurofibromatosis, may also be associated with pituitary deficiency (44). These tumours can be treated with targeted radiotherapy, which may also cause pituitary deficiency (45).

Histiocytosis: The infiltritative lesion of histiocytosis typically involves the hypothalamus and causes diabetes insipidus. Tumours are usually seen in the pituitary stalk and these lesions may resolve with chemotherapy. In approximately 30% of cases this will be associated with anterior pituitary deficiencies (46).

Cranial irradiation

All children who have received CNS irradiation, whether for prophylaxis for leukaemia, for tumours distant from or adjacent to the hypothalamic-pituitary region or during total body irradiation, are at some risk for the development of GHD (47-49). The sensitivity of the hypothalamo-pituitary axis to irradiation is dependent on the total dose, fractionation of irradiation, tissue localisation and the age of the patient. These patients require close endocrine monitoring and long-term follow-up. It can be anticipated that children who have received irradiation as primary or adjunctive therapy for solid tumours in the hypothalamic region will present with hypothalamic-pituitary dysfunction. Within 5 years of receiving doses greater than 30Gy, more than 85% of children will have documented GHD (47-49).

Investigations

Physiological tests:

GH profiles

In order to further elucidate GH dynamics in children, several studies have evaluated the usefulness and accuracy of 24h GH profile in the investigation of children with severe short stature (50). The information derived from such studies has proven that 24-h GH profiles are useful in determining the integrated secretion of GH (51). More importantly it allows for a detailed analysis of the dynamics of GH secretion. Although 12h or 24h GH profiles provide accurate information, performing such tests is clinically impractical, time consuming and costly.

Pharmacological tests:

GH stimulation tests: Due to pulsatile secretion GH levels are often low during much of a 24h period. Therefore GHD cannot be diagnosed with a random blood sample for GH measurement. The GH stimulation test was established to assess the maximum serum GH concentration that can be released in response to a pharmacological stimulus. There are many pharmacological agents which will induce GH release and some of them will also stimulate ACTH secretion causing an increase in serum cortisol.

There is an extensive literature on the relative advantages and disadvantages of the different GH stimulation tests (52-54). The insulin-tolerance test (ITT) is less used in the paediatric endocrine services in the UK because of the risk of serious hypoglycaemia, although in experienced units the ITT is safe. This test probably provides the best-validated stimulus for GH secretion (53). However, it should not be performed in children under 5 years of age. At present the most common tests used in paediatric endocrine practice in the UK are the glucagon and the clonidine tests (52) in which a peak GH level of <15mU/L during a well performed test is consistent with the diagnosis of GHD.

Serum markers of GH secretion:

IGFs and IGF-binding proteins: The clinical usefulness of measuring markers of growth hormone (GH) action such as IGF-I, IGFBP-3 and ALS in patients with disorders of GH secretion has been widely reported (55, 56). The clinical value of single measurements of IGF-I, IGFBP-3, IGFBP-2 and ALS, alone or in combination, in children with GHD have proven to be useful biochemical tools in confirming the clinical diagnosis (55, 56).

Radiological investigations

Radiological investigations include magnetic resonance imaging (MRI) of the brain and bone age for skeletal maturation determination. Molecular investigations of the GH gene and of other candidate genes such as GHRHR or homeodomain genes should be considered in children with familial GHD or in children with sporadic forms of classical GHD, in particular in children with multiple pituitary hormone deficiency.

Treatment

After a diagnosis of GHD has been confirmed the treatment is relatively simple, using human recombinant GH replacement therapy with daily subcutaneous injections. If the diagnosis of multiple hormone deficiency has been made, replacement therapy with appropriate doses of hydrocortisone and thyroxine is initiated before starting GH therapy.

The main therapeutic objectives of GH therapy in children with GHD are to normalise height during childhood and to reach normal adult height (Figure 1). In 2000 the Growth Hormone Research Society published the Consensus Guidelines for the diagnosis and treatment of children and adolescents with GHD (57). A recent comprehensive review of growth hormone treatment in GHD children carefully documented the published studies, which have formed the basis for the recommendation of GH treatment of children and adolescents with GHD (58). The best final height results reported to date were obtained with a GH dose between 0.2mg/kg/week (29µg/kg/day, 0.6IU/kg/week) and 0.3mg/kg/week (43µg/kg/day, 0.9IU/kg/week) (57-60).

Figure 1. Growth chart of a patient with growth hormone deficiency before and during treatment with GH.

Further studies are needed to determine the effect of GH titration, based for example on IGF-I adjustments. These studies may define optimal dose adjustment require to achieve optimal growth before and during puberty.

Safety issues regarding the effects of GH therapy in children have also been carefully monitored and adverse events and potential adverse events widely investigated (57-61).

The collective data from clinical experience on the use of rhGH replacement therapy in children and adolescents have demonstrated the overall safety of this treatment. Treatment with GH may unmask underlying hypothyroidism but significant side effects of GH treatment in children are very rare. These include benign intracranial hypertension, prepubertal gynecomastia, arthralgia, and oedema. Headaches may be the only symptom of intracranial hypertension in children (61). Patients on GH treatment complaining of headaches require carefully monitoring. Management of these side effects may include either transient reduction of dosage or temporary discontinuation of GH (61-63).

In the absence of other risk factors, there is no evidence that the risk of leukaemia or brain tumour recurrence is increased in patients who have received long-term GH treatment (57-61, 64).

Children with organic causes of GHD have an increased frequency of slipped capital femoral epiphysis (65-68) and require close monitoring for limp or pain in the lower extremity. Monitoring should also include careful evaluation of scoliosis, as progression of scoliosis has also been reported.

Finally, susceptibility to hypoglycaemia due to abnormalities in glucose homeostasis can be part of the clinical presentation of GHD (60). GH therapy decreases insulin sensitivity in a dose-dependent manner (69). Data from only one pharmaco-epidemiological study has reported that 43 children from a total database of 23 333 children receiving GH treatment presented with disorders of glucose homeostasis (70). In addition, there are a few reported cases of diabetes mellitus presenting while patients were on GH treatment (60). Currently, children receiving GH treatment are and will continue to require long-term surveillance to determine if GH treatment is associated with increased risk of diabetes type 2.

GH INSENSITIVITY SYNDROMES

Pathogenesis

The term of GH insensitivity syndrome (GHIS) describes a group of inherited disorders characterised by a reduction in the biological effects of GH in the presence of normal or elevated serum GH concentrations.

The first report of GHIS of genetic origin was published by Laron et al in 1966 (17). Since then the description of this disorder has expanded, as has the spectrum of clinical and biochemical abnormalities. The clinical disorder known as Laron syndrome has been shown to be associated with defects of the GHR gene (71). Due to the large number of established GHR mutations it is impossible to describe them all in this chapter but this topic has been recently reviewed in great detail (72).

Clinical presentations

The clinical characteristics of the affected patients are very similar to those seen in GH deficiency secondary to mutations in the GH gene, namely hypoglycaemic episodes, severe growth failure and a typical craniofacial appearance (Figure 2). In terms of linear growth, the most striking feature is the rapid decrease in height SDS during the early post-natal years. In the first three years of life there is a loss of approximately 3 SDS per year as demonstrated in the Ecuadorian patients, the largest kindred with this disorder (73). Intellectual retardation has been described in the original Israeli populations but is not a universal finding.

Figure 2. Photograph of a patient with the classical facies of Laron Syndrome (GHIS).

The heterogeneity of clinical and biochemical features has been demonstrated in a series of patients studied in Europe (74). A recent analysis has been performed of 59 of the patients in this European series who were classified into "classical" or atypical based on their facial appearance. Fifty patients had classical facial features whereas seven patients classified as "atypical" had normal facies (75). In addition, patients with atypical GHIS had less height deficit (height SDS -4.0 +/- 1.4) compared with patients with classical GHIS (-8.6+/-2.4).

Investigations

Severe short stature with or without classical features of Laron syndrome with normal to high serum GH concentrations, very low serum IGF-I, IGFBP-3 and ALS levels suggest impaired GH effects as described earlier. GH binding protein (GHBP), the circulating form of the extracellular domain of the GHR, was initially found to be absent but recent reports have found that some patients with GHIS may have normal or even elevated serum GHBP (74). Usually more atypical patients had normal GHBP.

The molecular defect in GHIS originates in the GHR gene, with over 30 mutations now reported. The majority of the molecular defects of the GHR have been point mutations in exons 2-7 of the GHR gene, which encodes the extracellular domain of the receptor and therefore these mutations impaired GH binding (74).

TREATMENT

We have gained new insights into the growth-promoting and metabolic actions of IGF over the last few years primarily from studies of children with GHIS (70-78). Prolonged therapy with rhIGF-I to children with GHIS and to those with GH gene deletion has proved to be safe and effective with side effects presenting mainly when high doses of rhIGF-I have been used. However, treatment with rhIGF-I given systemically may not completely replace the local response of target tissues to locally produced IGF-I (78).

CONCLUSIONS

The integrity of the GH-IGF-I axis is essential for normal linear growth in childhood. Defects in either GH secretion or action will result in reducing serum IGF-I, the key growth promoting peptide.

The identification of several new genetic causes of GH deficiency or insensitivity has broadened the range of aetiologies responsible for GH disorders. While classical endocrine tests remain the most reliable for assessing the GH-IGF-I axis, analysis of the appropriate candidate genes can contribute to the precise definition of the pathogenesis of the growth disorder.