Introduction

Growth failure in β thalassaemia major (TM) has been recognised for many years, and has persisted despite major therapeutic advances (De Sanctis et al., 2013; Toumba et al., 2007).

In the past, prevalence of growth failure and short stature in children with thalassemia varied from 30 to 60% in most studies (Table 1). In the current era, the adherence to modern transfusion and iron chelation protocols and avoidance of iron chelator overdosage has clearly reduced the risk of short stature and may have potentially enhanced endocrine development in children with TM.

Table 1

Prevalence of short stature (< 3° percentile) in thalassaemia.

The short stature encountered in thalassaemia is often disproportionate with a low upper segment to lower segment ratio. The exact reason is not clear and an interplay of multiple factors is responsible, factors such as iron overload (impaired cartilage growth), early use of desferrioxamine (DFO) for chelation and delayed puberty/hypogonadism (De Sanctis et al., 2013).

The child with TM has a particular growth pattern, which is relatively normal until age 9-10 years; after this age a slowing down of growth velocity and reduced or absent pubertal growth spurt are observed. The pathogenesis of growth failure is multifactorial. The fundamental problem is the free iron and haemosiderosis-induced damage of the endocrine glands. Additional factors may contribute to the aetiology of growth delay including chronic anaemia and hypoxia, chronic liver disease, zinc, folic acid and other nutritional deficiencies, intensive use of chelating agents, emotional factors, endocrinopathies (hypogonadism, delayed puberty, hypothyroidism, disturbed calcium homeostasis and bone disease) and dysregulation of the growth hormone – insulin-like growth factor 1 axis (GH-IGF-1) (Figure 1) (Skordis & Kyriakou, 2011).

Figure

Three phases of growth disturbances according to age of presentation are well recognised, and have different aetiologies: in the first phase growth disturbance is mainly due to hypoxia, anaemia, ineffective erythropoiesis and nutritional factors. During late childhood (second phase), growth retardation is mainly due to iron overload affecting the GH-IGF-1 axis and other potential endocrine complications (Table 2). After the age of 10-11 years (third phase), delayed or arrested puberty is an important contributing factor to growth failure in adolescent thalassaemics, who do not exhibit a normal growth spurt (Figure 2).

Table 2

Prevalence of growth hormone deficiency in children, adolescents and young adults with thalassaemia.

Figure 2

Typical growth curve in a boy with thalassaemia major.

Assessment of personal history in a thalassaemic child with short stature or poor growth velocity/year

The following points should be taken into consideration:

• Onset of disease and the need for blood transfusions. Patients with the β0/β0 genotype have a significantly higher prevalence of growth retardation compared to those with the β0 /β+ and β+ /β+ genotypes.
• Pre-transfusion haemoglobin level
• Annual packed red blood cells requirement
• Chelation therapy (type, dose, compliance)
• Serum ferritin levels
• Associated comorbidities (endocrine complications, chronic liver disease, chronic cardiac failure, human immunodeficiency virus (HIV) infection).

Diagnosis and investigations

Diagnosis requires careful clinical evaluation to establish:

• Short stature – height below the 3rd centile for sex and age (based on national growth charts), and/or
• Slow growth rates – growth velocity expressed in cm/year, below the 10th centile for age and sex (based on growth velocity charts), and /or
• Signs of other pituitary hormone deficiencies (e.g. gonadotrophins, growth hormone, central hypothyroidism)
• Signs of other possible causes of retarded growth (nutritional deficiencies, chronic hepatic disease, chronic heart failure).

The first step in the management of short stature or retarded growth is the regular (six-month intervals) and accurate measurement of standing and sitting height (Figure 3) and pubertal staging (Figure 4). Growth data are plotted on ethnically adjusted charts or internationally (World Health Organization) adjusted charts. Interpretation of absolute height must consider the height of the parents.

Figure 3

Measurements of standing height and sitting height with Harpenden stadiometer in absence of sitting height table.

Figure 4

Pubertal assessment in males and females according to Tanner. For the male figure, the (average) size of the testis [cm] and the capacity in mL is indicated. (Source: Dr Michał Komorniczak (Poland).

In subjects with disproportionate short stature, radiographs of tibia and spine to exclude the presence of platylospondylosis or metaphyseal cartilaginous dysplasia changes (Figure 5).

Figure 5

Platyspondylosis of the vertebral bodies in a thalassaemia major patient.

Annual growth screening

This should be started from the age of 9 years, or earlier if clinically indicated. The following tests and assessments are recommended:

1. Serum thyroid stimulating hormone (TSH) and free thyroxine (FT4).
2. Serum calcium, ionised calcium, inorganic phosphate, magnesium and alkaline phosphatase.
3. Serum IGF-1 and insulin-like growth factor-binding protein 3 (IGF BP-3) in growth screening are useful indicators of growth hormone secretion and nutrition, bearing in mind that chronic liver diseases and malnutrition may interfere with their secretion.
4. Serum zinc (in selected cases).
5. Screening for coeliac disease.
6. X-ray of wrist and hand, tibia and spine should be evaluated in patients with TM who have body disproportion to exclude the presence of platylospondylosis or metaphyseal cartilaginous dysplasia changes.
7. Assessment of growth hormone (GH) secretion: significant GH insufficiency may be diagnosed by a reduced response of GH to two provocative tests (GH peak <10 ng/ml) in children and adolescents and 3 ng/ml in adults). A list of the classification of the GH-IGF disorders is given in Figure 7.
8. Magnetic resonance imaging (MRI) of the hypothalamic–pituitary region is useful to evaluate pituitary iron overload as well as the size of pituitary gland (atrophy).
9. Luteinising hormone (LH), follicle-stimulating hormone (FSH) and sex steroids, starting from the pubertal age.

Figure 7

Practical approach to the treatment of growth retardation in thalassaemia. Reproduced with permission from Soliman et al. (2013).

Figure 6

Level of defect in the GH-IGF 1 axis in thalassaemia. GH, growth hormone; IGF, insulin-like growth factor.

At present, there are no guidelines in the literature for the assessment of GH in adult patients with TM. The American Association of Clinical Endocrinologists (AACE) advises that one GH stimulation test is sufficient if clinical suspicion is high, such as in patients with at least one other pituitary hormone deficiency and low or low-normal IGF 1 level. However, in patients with TM and chronic liver disease, IGF 1 levels are low and may have a low diagnostic sensitivity for growth hormone deficiency (GHD) (Soliman et al., 1999).

GHD in adults is a clinical syndrome associated with lack of positive well-being, depressed mood, feelings of social isolation, decreased energy, alterations in body composition with reduced bone and muscle mass, diminished exercise performance and cardiac capacity and altered lipid metabolism with increase in adiposity (Soliman et al., 2013).

In patients with chronic diseases, the clinical evaluation of GHD is difficult because signs and symptoms may be subtle and nonspecific, and universal provocative testing in all patients is difficult because the approach is cumbersome and expensive. In addition, TM patients with GHD may have deficiencies of other pituitary hormones, further complicating the clinical picture. This contrasts with childhood-onset GHD where growth failure acts as a useful biological marker of GHD.

Treatment

Prevention and treatment of growth abnormalities in patients with TM should include (Figure 7):

• Adequate blood transfusion to maintain pretransfusion haemoglobin level >90 g/l.
• Adequate chelation to attain serum ferritin < 1,000 ng/ml.
• Use of new iron-chelators with lower toxicity on the skeleton and with better patient compliance.
• Correction of nutritional deficiencies (protein-calorie, folate, vitamin D, vitamin A, zinc, carnitine) when suspected.
• Oral zinc sulphate supplementation should be given to patients with proven deficiency.
• Correction of hypersplenism.
• Appropriate and timely management of pubertal delay in boys and girls with TM and appropriate induction of puberty to attain normal pubertal growth spurt and normal bone accretion.
• Accurate diagnosis and early management of hypothyroidism and abnormal glucose homeostasis (impaired glucose tolerance and diabetes mellitus).
• The management of GHD has been a matter of debate. The linear growth velocity attained after exogenous GH administration in children with thalassaemia is reported to be lower than that seen in children with primary GH deficiency, possibly due to GH insensitivity (De Sanctis & Urso, 1999; Soliman, Khalafallah & Ashour, 2009). Therefore, large well-designed randomised controlled trials over a longer period with sufficient duration of follow up are needed (Ngim et al., 2017).
• At present, there are no guidelines in the literature for the use of recombinant human GH in adult patients with TM and GHD. However, due to the possible positive effects of GH on the heart, it could be speculated that GH treatment may be useful in some patients with cardiac failure (Erfurth et al., 2004; Smacchia et al., 2012).
• During GH treatment, patients should be monitored at 3-4 monthly intervals with a clinical assessment and an evaluation for parameters of GH response and adverse effects (De Sanctis & Urso, 1999).

Box

Summary.

References

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