Growth disorders and acromegaly

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Growth disorders and acromegaly

Normal growth

Growth in children can be divided into three stages (Fig 43.1). Rapid growth occurs during the first 2 years of life; the rate is influenced by conditions in utero, as well as the adequacy of nutrition in the postnatal period. The next stage is relatively steady growth for around 9 years and is controlled mainly by growth hormone (GH). If the pituitary does not produce sufficient growth hormone, the yearly growth rate during this period may be halved and the child will be of short stature. The growth spurt at puberty is caused by the effect of the sex hormones in addition to continuing GH secretion. The regulation of GH secretion is outlined in Figure 43.2.

Fig 43.1 Median height velocity curve for boys and girls showing the three growth stages.

Fig 43.2 The normal regulation of GH secretion.

GH is only one of many hormones involved in growth. Insulin-like growth factors, thyroxine, cortisol, the sex steroids and insulin are also involved.

Growth hormone insufficiency

Any child whose height for age falls below the 3rd centile on a standard chart, or who exhibits a slow growth rate, requires further investigation. If GH deficiency is diagnosed, and treatment is required, then the earlier it is given the better the chance that the child will eventually reach normal size.

Growth hormone insufficiency is a rare cause of impaired physical growth. It is important to differentiate between children whose slow growth or growth failure is due to illness or disease and those whose short stature is a normal variant of the population. Causes of short stature are:

having parents who are both short

inherited diseases such as achondroplasia, the commonest cause of severe dwarfism

systemic chronic illness, such as renal disease, gastrointestinal disorders or respiratory disease

psychological factors such as emotional deprivation

hormonal disorders.

Standard graphs relating age and height are available for the normal population. Accurate measurements of height should be made to establish whether a child is small for chronological age. These measurements are repeated after 6 and 12 months to assess the growth rate. The height of the parents should also be assessed. The bone age is the best predictor of final height in a child with short stature; this is determined by radiological examination of hand and wrist. In most growth disorders bone age is delayed and by itself is of little diagnostic value, but taken together with height and chronological age, a prediction of final height may be obtained.

Clinical note

In the investigation of normal looking children with short stature, coeliac disease must always be considered. The diagnosis is frequently overlooked.

Tests of growth hormone insufficiency

Growth hormone deficiency may be present from birth or due to later pituitary failure. A variety of stimulation tests have been used to evaluate GH deficiency. Serum GH concentrations rise in response to exercise, and this may be used as a preliminary screening test. They also rise during sleep, and high concentrations in a nocturnal sample may exclude GH deficiency. The lack of GH response to the stress of exercise or clonidine, a potent stimulant of GH secretion, is diagnostic. Some centres have now abandoned the use of insulin-induced hypoglycaemia as a diagnostic test in children because of its hazards, and instead use the arginine stimulation test.

The GH response to stimulation requires the presence of sex steroids. Thus, prepubertal children, and hypogonadal adults, require ‘priming’ by the administration of either testosterone or oestrogen before GH reserve is assessed.

Increasingly, urinary growth hormone measurements are being used to assess possible GH lack in children. Random serum IGF 1 determinations may be of value. Levels within reference limits exclude GH deficiency.

Treatment

Genetically engineered GH is available and is used in the treatment of that small group of children with proven GH deficiency.

Excessive growth

Growth hormone excess in children is characterized by extremely rapid linear growth (gigantism). The condition is uncommon and is most often due to a GH secreting pituitary tumour. Other causes of tall stature in children are rare and include:

Hyperthyroidism. An increased growth rate, with advanced bone age, is a feature of hyperthroidism in children, or hypothyroid children over-replaced with thyroxine.

Inherited disorders such as Klinefelter’s syndrome (a 47 XXY karyotype). The relative deficiency of testosterone is associated with delayed epiphyseal closure.

Congenital adrenal hyperplasia. (CAH may cause rapid somatic growth in children, but usually leads to suboptimal adult height due to premature epiphyseal closure, as a result of androgen excess.)

Acromegaly

Increased GH secretion later in life, after fusion of bony epiphyses, causes acromegaly (Fig 43.3). The most likely cause is a pituitary adenoma. Clinical features include:

Fig 43.3 Clinical picture of an acromegalic patient.

coarse facial features

soft tissue thickening, e.g. the lips

characteristic ‘spade-like’ hands

protruding jaw (prognathism)

impaired glucose tolerance or diabetes mellitus.

Diagnosis

Formal diagnosis of acromegaly requires an oral glucose tolerance test with GH measurement (see pp. 82–83). Acromegalic patients do not suppress fully in response to hyperglycaemia (Fig 43.4), and indeed in some patients a paradoxical rise in GH may be observed.

Fig 43.4 The response of GH in a glucose tolerance test in a normal and acromegalic patient.

IGF 1 is produced in response to GH and provides useful additional biochemical information. It is now routinely measured in the diagnosis and especially monitoring of treated acromegaly, with an elevated level suggestive of active disease. Other measurements, e.g. IGF binding protein 3 (IFGBP3), have not yet attained widespread clinical use.

Treatment

Surgery. Trans-sphenoidal hypophysectomy is the first-line treatment for most acromegalic patients. Its success depends on the size of the tumour.

Radiation. This is usually reserved for patients whose disease remains active despite surgery. It may take years after pituitary irradiation before safe levels of GH are achieved. Medical treatment is required in the interim.

Medical. Dopamine agonists like bromocriptine were widely used in the past, but response rates were low. The advent of long-acting synthetic analogues of somatostatin, such as octreotide, has transformed the medical management of acromegaly. These are expensive drugs with side effects, and it is sensible to screen patients for responsiveness by measuring GH after administering octreotide (octreotide suppression test).

Case history 33

James is 5 years old and is much smaller than his classmates at school. His growth rate has been monitored and has clearly dropped off markedly in the past year. He is an active child, and on examination has normal body proportions. His mother and father are of average height. His bone age is that of a 3-year-old child.

• What biochemical tests would be appropriate in the investigation of this boy?

Comment on page 167.

Growth disorders and acromegaly

GH deficiency is a rare cause of short stature in children, and is investigated only after other causes of short stature have been eliminated.

Diagnosis of GH deficiency is made on the failure of serum GH to rise in response to stimuli.

Gigantism in children is caused by increased GH secretion, usually from a pituitary tumour. Acromegaly is the consequence of increased GH secretion in adults.

Lack of suppression of serum GH levels in response to a glucose tolerance test is the diagnostic test for acromegaly.

Serum IGF 1 concentrations are of value in the diagnosis of acromegaly and the monitoring of treatment.

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