**2. Growth and development in thalassaemia**

From the foetal, through to infantile, pre-pubertal period and puberty, children with thalassaemia exhibit delayed growth [9]. It is estimated that 20–30% of these children and adolescents are affected by growth hormone (GH) deficiency [10]. In the remainder of thalassaemic patients without overt growth hormone deficiency, provocative testing—for example clonidine or glucagon stimulation tests—suggests that peak GH levels are lower than seen in constitutive short stature. Dhouib et al. recently showed a 35% incidence of GH deficiency in a Tunisian paediatric cohort [11]. Multiple causes for growth failure have been posited. These include features directly related to iron overload, including free radical toxicity [12]; damage to other endocrine axes, including the GH/Insulin-like growth factor (IGF-1) axis [13], pubertal delay and hypothyroidism; and complications of therapy, including chelation agent, particularly desferrioxamine, toxicity [14]. Hepatic cirrhosis, anaemia and zinc deficiency have also been implicated [15].

The anterior pituitary gland is particularly vulnerable to oxidative stress caused by free radicals, with even modest levels of iron deposition, detected by magnetic resonance imaging (MRI), disrupting its function [12]. Comparative studies of diurnal hormone secretion suggest that the 24-hour profile of GH secretion, and the response growth hormone releasing hormone (GHRH, secreted by the arcuate nucleus of the hypothalamus), in thalassaemic patients is similar that of children with idiopathic short stature [16]. It is posited that thalassaemia major may be associated with increased somatostatin tone, with subsequent disruption of GH secretion [17].

Thalassaemia major may be characterised by relative growth hormone deficiency, implied by the low levels of serum IGF-1 but normal GH reserve seen in patients. The positive therapeutic response seen with exogenous GH supplementation implies that, at the post-receptor level, this resistance may only be partial [18]. Anaemia, ineffecient erythropoiesis and chelation therapy also inhibits linear growth in children with thalassaemia major. Desferrioxamine and pathologic iron deposition are proposed to disrupt local IGF-1 production and paracrine signalling at the growth plate [14], resulting in inhibition of cellular proliferation and mineral deposition. Truncal shortening and abnormal body proportions are frequently observed, and have been attributed to the disease process itself, compounded by iron and desferrioxamine toxicity [18]. Limited evidence is emerging that these phenomena may be at least partly contingent on the timing of initiation of chelation and its route of administration. Soliman and colleagues reported a cross-sectional cohort analysis of beta thalassaemia patients commenced on oral iron chelation (OIC) with desferoxamine either before (n = 15) or after (n = 40) attaining final adult height. In this small study, pre-pubertal initiation of OIC was correlated with increased final adult height, in parallel with a lower overall incidence of endocrinopathies and reduced hepatic iron deposition [19].

Karamifar et al. have demonstrated that 62.9% of girls and 69% of boys affected with thalassaemia were less than 2SD below the mean for normal height [20]. Sharma et al. studied an Indian cohort of beta-thalassaemic children on oral desferiprone, of whom 55% were of short stature and 27% had a height z-score less than −3 SD. In the subset with height z-score < −3 SD, 17 of 19 patients also had severely impaired GH induction in response to dynamic testing with clonidine [21]. In one cohort from Germany, 40.6% of patients were defined as being short in stature (final adult height < 3rd percentile/below 2 standard deviations [SD] from the mean) [22]. Soliman and colleagues replicated this observation, reporting short stature (<2SD) in 49% of their thalassaemic patients [23], whereas Borgna-Pignatti et al. reported short stature in 37% of their patients [24]. Moayeri et al. showed that

**63**

*Investigation and Management of Endocrinopathies in Thalassaemia Major*

62% were less than 2SD and 49% were 3SD below the mean and also confirmed decreased growth hormone response to two provocative tests and low levels of IGF-1 in a majority of their thalassaemic patients24. Similar reduced responses to provocative tests have been reported in studies led by Gulati et al. (51%) and Theodiris et al. (20%) [10, 25]. Interestingly, Soliman et al. report that in a small sample of adult patients on oral chelation therapy, IGF-1 expression levels did not differ significantly between those with normal GH levels and those with GH deficiency, despite significantly lower final adult height in the GH deficient group [19]. Although the results of short term GH therapy are encouraging, the impact of treatment on final height of non-GH deficient thalassaemic children remains uncertain [18] and often GH produces uncertain clinical response [26, 27]. Ngim et al. have undertaken a Cochrane Systematic Review of GH replacement in thalassaemia. A single non-randomised trial was eligible, which enrolled 20 Turkish children with beta-thalassaemia major, receiving either daily subcutaneous GH or standard care. It presented tentative evidence that height velocity may be increased with GH, but reported no significant differences in the height standard deviations between groups at the study end-point [28]. Most patients lack the pubertal spurt and have reduced GH peak amplitude [29], hence responses to recombinant human GH therapy is poor when compared with that of children with GH deficiency, idiopathic

The 2016 United Kingdom Thalassemia Society (UKTS) guidelines recommend stringent assessment of growth during childhood. This includes recording of height (both sitting and standing), weight and height velocity at six-monthly intervals until final adult height is attained [30]. Height deficits should prompt referral to a paediatric endocrinologist. Plain hand/wrist radiographs at 1–2 year intervals until fusion of the epiphyses may aid investigation of faltering height velocity [30]. Reduced height velocity, particularly around age 8–12 years, should prompt consideration of both desferrioxamine toxicity and GH deficiency, requiring GH stimula-

In contrast to GH deficiency in childhood, GH abnormalities in adults with thalassaemia are less well characterised. Recent data from an I-CETA survey (International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine) covering 3314 adult thalassaemia major patients across 15 international centres, reported a GH deficiency incidence of 3% [31]. The discrepancy between this figure and earlier estimates from paediatric cohorts is multifactorial. Unlike childhood growth failure, there is no obvious pathological correlate of adult growth hormone deficiency to prompt investigation. Adult GH deficiency can manifest with neuropsychiatric symptoms; abnormal body composition; and cardiac features, including both reduced exercise performance [32] and altered myocardial structure [33]. Soliman and colleagues have proposed criteria for GH deficiency screening in adults with thalassaemia major. These include individuals with high iron loads, short stature (height < −2.5 SDS), low serum IGF-1 (< −2 SDS) or existing cardiomyopathy [34]. Given increasing survival of patients with thalassaemia major into adulthood, this topic remains in

Sexual immaturity is a profound complication of severe thalassaemia [35]. Disruption of the hypothalamic–pituitary-gonadal axis (HPG) may result in infertility [36]. While hypogonadism can occur as a result of primary or secondary hypogonadism or as a combination of both, multiple studies have shown

*DOI: http://dx.doi.org/10.5772/intechopen.93861*

short stature or Turner Syndrome.

need of further investigation.

tion testing and supplementation if deficient [30].

**3. Hypogonadism and puberty in thalassaemia**

#### *Investigation and Management of Endocrinopathies in Thalassaemia Major DOI: http://dx.doi.org/10.5772/intechopen.93861*

*Human Blood Group Systems and Haemoglobinopathies*

**2. Growth and development in thalassaemia**

anaemia and zinc deficiency have also been implicated [15].

nopathies and reduced hepatic iron deposition [19].

From the foetal, through to infantile, pre-pubertal period and puberty, children with thalassaemia exhibit delayed growth [9]. It is estimated that 20–30% of these children and adolescents are affected by growth hormone (GH) deficiency [10]. In the remainder of thalassaemic patients without overt growth hormone deficiency, provocative testing—for example clonidine or glucagon stimulation tests—suggests that peak GH levels are lower than seen in constitutive short stature. Dhouib et al. recently showed a 35% incidence of GH deficiency in a Tunisian paediatric cohort [11]. Multiple causes for growth failure have been posited. These include features directly related to iron overload, including free radical toxicity [12]; damage to other endocrine axes, including the GH/Insulin-like growth factor (IGF-1) axis [13], pubertal delay and hypothyroidism; and complications of therapy, including chelation agent, particularly desferrioxamine, toxicity [14]. Hepatic cirrhosis,

The anterior pituitary gland is particularly vulnerable to oxidative stress caused by free radicals, with even modest levels of iron deposition, detected by magnetic resonance imaging (MRI), disrupting its function [12]. Comparative studies of diurnal hormone secretion suggest that the 24-hour profile of GH secretion, and the response growth hormone releasing hormone (GHRH, secreted by the arcuate nucleus of the hypothalamus), in thalassaemic patients is similar that of children with idiopathic short stature [16]. It is posited that thalassaemia major may be associated with increased somatostatin tone, with subsequent disruption of GH

Thalassaemia major may be characterised by relative growth hormone deficiency, implied by the low levels of serum IGF-1 but normal GH reserve seen in patients. The positive therapeutic response seen with exogenous GH supplementation implies that, at the post-receptor level, this resistance may only be partial [18]. Anaemia, ineffecient erythropoiesis and chelation therapy also inhibits linear growth in children with thalassaemia major. Desferrioxamine and pathologic iron deposition are proposed to disrupt local IGF-1 production and paracrine signalling at the growth plate [14], resulting in inhibition of cellular proliferation and mineral deposition. Truncal shortening and abnormal body proportions are frequently observed, and have been attributed to the disease process itself, compounded by iron and desferrioxamine toxicity [18]. Limited evidence is emerging that these phenomena may be at least partly contingent on the timing of initiation of chelation and its route of administration. Soliman and colleagues reported a cross-sectional cohort analysis of beta thalassaemia patients commenced on oral iron chelation (OIC) with desferoxamine either before (n = 15) or after (n = 40) attaining final adult height. In this small study, pre-pubertal initiation of OIC was correlated with increased final adult height, in parallel with a lower overall incidence of endocri-

Karamifar et al. have demonstrated that 62.9% of girls and 69% of boys affected with thalassaemia were less than 2SD below the mean for normal height [20]. Sharma et al. studied an Indian cohort of beta-thalassaemic children on oral desferiprone, of whom 55% were of short stature and 27% had a height z-score less than −3 SD. In the subset with height z-score < −3 SD, 17 of 19 patients also had severely impaired GH induction in response to dynamic testing with clonidine [21]. In one cohort from Germany, 40.6% of patients were defined as being short in stature (final adult height < 3rd percentile/below 2 standard deviations [SD] from the mean) [22]. Soliman and colleagues replicated this observation, reporting short stature (<2SD) in 49% of their thalassaemic patients [23], whereas Borgna-Pignatti et al. reported short stature in 37% of their patients [24]. Moayeri et al. showed that

**62**

secretion [17].

62% were less than 2SD and 49% were 3SD below the mean and also confirmed decreased growth hormone response to two provocative tests and low levels of IGF-1 in a majority of their thalassaemic patients24. Similar reduced responses to provocative tests have been reported in studies led by Gulati et al. (51%) and Theodiris et al. (20%) [10, 25]. Interestingly, Soliman et al. report that in a small sample of adult patients on oral chelation therapy, IGF-1 expression levels did not differ significantly between those with normal GH levels and those with GH deficiency, despite significantly lower final adult height in the GH deficient group [19].

Although the results of short term GH therapy are encouraging, the impact of treatment on final height of non-GH deficient thalassaemic children remains uncertain [18] and often GH produces uncertain clinical response [26, 27]. Ngim et al. have undertaken a Cochrane Systematic Review of GH replacement in thalassaemia. A single non-randomised trial was eligible, which enrolled 20 Turkish children with beta-thalassaemia major, receiving either daily subcutaneous GH or standard care. It presented tentative evidence that height velocity may be increased with GH, but reported no significant differences in the height standard deviations between groups at the study end-point [28]. Most patients lack the pubertal spurt and have reduced GH peak amplitude [29], hence responses to recombinant human GH therapy is poor when compared with that of children with GH deficiency, idiopathic short stature or Turner Syndrome.

The 2016 United Kingdom Thalassemia Society (UKTS) guidelines recommend stringent assessment of growth during childhood. This includes recording of height (both sitting and standing), weight and height velocity at six-monthly intervals until final adult height is attained [30]. Height deficits should prompt referral to a paediatric endocrinologist. Plain hand/wrist radiographs at 1–2 year intervals until fusion of the epiphyses may aid investigation of faltering height velocity [30]. Reduced height velocity, particularly around age 8–12 years, should prompt consideration of both desferrioxamine toxicity and GH deficiency, requiring GH stimulation testing and supplementation if deficient [30].

In contrast to GH deficiency in childhood, GH abnormalities in adults with thalassaemia are less well characterised. Recent data from an I-CETA survey (International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine) covering 3314 adult thalassaemia major patients across 15 international centres, reported a GH deficiency incidence of 3% [31]. The discrepancy between this figure and earlier estimates from paediatric cohorts is multifactorial. Unlike childhood growth failure, there is no obvious pathological correlate of adult growth hormone deficiency to prompt investigation. Adult GH deficiency can manifest with neuropsychiatric symptoms; abnormal body composition; and cardiac features, including both reduced exercise performance [32] and altered myocardial structure [33]. Soliman and colleagues have proposed criteria for GH deficiency screening in adults with thalassaemia major. These include individuals with high iron loads, short stature (height < −2.5 SDS), low serum IGF-1 (< −2 SDS) or existing cardiomyopathy [34]. Given increasing survival of patients with thalassaemia major into adulthood, this topic remains in need of further investigation.
