Endocrinology and metabolism

Published on 21/03/2015 by admin

Filed under Pediatrics

Last modified 22/04/2025

Print this page

This article have been viewed 1284 times

12 Endocrinology and metabolism

Nandu Thalange, Richard Beach

Introduction

The body maintains stability of its many functions by means of a complex network of control systems. Such controls are present in every system controlling e.g. heart rate, respiration and body temperature. This chapter is concerned with the systems that regulate the body’s endocrine and metabolic functions, and how they are affected by disease.

Regulating blood glucose

Glucose is a key energy-providing substrate for the body’s metabolism – especially the brain. Insulin produced by the pancreatic beta cells controls the flow of glucose into cells and is produced in response to hyperglycaemia.

Hypoglycaemia results in release of glucagon, cortisol and adrenaline (epinephrine) with resultant gluconeogenesis and release of glucose from glycogen stores.

Glucose measurement is conveniently performed at the bedside on a capillary blood sample using a blood glucose meter. These meters greatly simplify assessment of children with suspected hypo- or hyperglycaemia.

Hypoglycaemia

Significant hypoglycaemia – defined as blood glucose <2.6 mmol/L (as in Case 12.1) – is rare outside the neonatal period. The symptoms of altered consciousness, pallor and sweatiness are secondary to impaired cerebral metabolism (neuroglycopenia) and adrenaline (epinephrine) release. After a period of fasting, blood glucose levels fall, insulin secretion is suppressed and lipolysis leads to ketone body production. Thus, ketosis during fasting is a normal physiological response. This response is exaggerated in ketotic hypoglycaemia, and ketones rise to toxic levels causing severe acidosis, in addition to the presence of hypoglycaemia, as in Case 12.1. Affected children may have recurrent episodes during illness or after exercise. Treatment is with additional high-energy snacks and carbohydrate-containing drinks at bedtimes and during illness.

Case 12.1

A boy with hypoglycaemia

A 4-year-old boy presented with a 12-hour history of drowsiness, vomiting and sighing respiration. He was pale, sweaty and confused but circulation was normal with no evidence of shock or dehydration. His blood glucose was 1.0 mmol/L and blood ketones (beta-hydroxybutyrate) 5.6 mmol/L (normal <1.0). After treatment with 5 mL/kg of 10% dextrose he recovered to an alert, albeit irritable, state. The vomiting and ketosis resolved over a few hours of intravenous dextrose therapy. His parents recalled repeated episodes of vomiting and lethargy in the past.

Hypoglycaemia with ketosis also occurs with hypopituitarism and primary and secondary adrenal insufficiency secondary to growth hormone and/or cortisol deficiency. Metabolic causes include glycogen storage diseases, fatty acid disorders, galactosaemia and fructose intolerance. Absence of ketones with hypoglycaemia implies the presence of insulin; this occurs with dysregulated insulin secretion as occurs in persistent hyperinsulinaemic hypoglycaemia of infancy, or insulinoma, or exogenous insulin administration as in diabetes.

Diabetes

Type 1 diabetes mellitus results from progressive immune-mediated destruction of insulin-producing pancreatic beta cells, as in Case 12.2. It is increasingly common in children (0.2% of children under 16 years), and the mean age of diagnosis is falling. Insulin deficiency results in progressive hyperglycaemia, weight loss, polydipsia and polyuria (as in Case 12.2). Rapid lipolysis results in production of acidic ketone bodies (ketosis), and ultimately diabetic ketoacidosis, if the symptoms of diabetes are not recognized. For management of diabetic ketoacidosis, see Appendix I, p. 290.

When diabetes is suspected, it is imperative to measure blood glucose. If diabetes is confirmed (random glucose >11.1 mmol/L), then prompt referral to the local diabetes team is indicated, even if the child seems well, as deterioration may be rapid.

Case 12.2

A girl with hyperglycaemia

A 7-year-old girl had been lacking in energy for a month or so and losing weight. For a week she seemed thirsty all the time and was awake at night, drinking and passing large amounts of urine. On the day of admission she had abdominal pain and had vomited once. On examination she had clearly lost some weight but there was no circulatory compromise. Her blood glucose was 19.6 mmol/L with blood ketones of 0.5 mmol/L, thus excluding diabetic ketoacidosis. Islet cell antibodies were found on investigation, confirming type 1 diabetes.

In hospital, it is now routine to assess blood ketones (beta-hydroxybutyrate) using a rapid bedside test. This is very helpful in identifying the child with ketoacidosis and gives a result within minutes. Blood ketones above 3.0 mmol/L indicate the potential for ketoacidosis, which is confirmed by blood gas testing. Particularly in the very young, symptoms of diabetes may be difficult to spot. Ketosis may induce abdominal pain and vomiting which may be mistaken for gastroenteritis, and hyperventilation secondary to metabolic acidosis (‘Kussmaul respiration’) may be mistaken for asthma or pneumonia.

After diagnosis, the key goals are to teach the child and parents to administer insulin and to perform blood glucose testing. Insulin administration is facilitated by modern insulin pens and, in the younger child, pens which can administer insulin in ½ unit increments. Blood glucose monitoring should be made integral to insulin therapy, and parents and children should be encouraged to adjust insulin doses from the outset. With conventional ‘human’ insulins, it is necessary to wait 20–30 minutes before eating, but with newer rapid-acting insulin analogues this is unnecessary. Modern intensive insulin regimes use a once-daily injection of long-acting ‘basal’ insulin and mealtime boluses of quick-acting insulin (‘basal-bolus’). This allows flexible mealtimes and insulin dosing adjusted to carbohydrate intake, and is particularly suitable for older children and teenagers with diabetes. Insulin infusion pumps are a refinement of the basal-bolus technique, and are increasingly being used in the UK.

Diet

Dietary management of diabetes boils down to a healthy diet, with low sugar choices, comprising regular meals and appropriate snacks before exercise. Ideally, carbohydrate should contribute 45–60% of energy needs, primarily as unrefined complex carbohydrate. Fat intake should be moderated to a maximum of 35% of energy intake. Dietetic help is vital in managing the child at diagnosis.

Control

The management of diabetes requires a team approach using the skills of the paediatrician, diabetes specialist nurse, dietitian, psychologist, and of course the parents and child, to achieve the best results. The quality of diabetes control may be judged from home blood glucose measurements and measurement of glycated haemoglobin A₁ (HbA_1C). HbA_1C provides an integrated measure of glycaemic control over 2 to 3 months. Above the target of 48–58 mmol/mol (6.5–7.5%) for each 10–15 mmol/mol rise in HbA_1C complication risk increases by 30%. Good glycaemic control reduces the long-term risk of microvascular complications of diabetes: nephropathy, retinopathy and neuropathy, and macrovascular disease – ischaemic heart disease, strokes and peripheral vascular disease. Management is geared to attaining the lowest practicable HbA_1C for each individual, taking into account what is realistic and achievable for them.

Complications and co-morbidity

Hypoglycaemia is part of life for children with diabetes. Mild hypoglycaemia in which the patient feels ‘low’ occurs commonly in a well-controlled diabetic, but moderate and severe hypoglycaemia should be avoided if possible. Moderate hypoglycaemia induces irritability and autonomic symptoms: sweating, pallor, tachycardia. Recurrent episodes of hypoglycaemia cause loss of hypoglycaemic awareness and greatly increase the risk of severe hypoglycaemia. Severe hypoglycaemia, characterized by collapse, coma or seizures secondary to neuroglycopenia, requires third-party assistance. Treatment of mild and moderate hypoglycaemia is with glucose in the form of food, drink or dextrose tablets or oral glucose gel. Severe hypoglycaemia requires prompt administration of oral glucose gel (not in unconscious or fitting patients), intramuscular glucagon, or, if practicable, intravenous glucose.

Screening for microalbuminuria and elevated blood pressure should be undertaken at least annually from diagnosis. Microalbuminuria is an early marker of diabetic nephropathy. Screening for diabetic retinopathy should commence annually from 12 years of age, ideally with retinal photography. In adults, it is recognized that blood pressure and lipid levels also contribute to complication risk. Trials of therapy are under way to determine whether adolescents may benefit from antihypertensive and lipid-lowering therapies.

Growth may be impaired, particularly if there is marked non-compliance with therapy, and height and weight should be plotted at each visit to the clinic.

Annual thyroid function testing is recommended for all children with diabetes, due to the high incidence of autoimmune thyroid disease. Coeliac screening is recommended at diagnosis. Some centres continue to screen for coeliac disease 3-yearly, but this falls outside current NICE guidance on screening for coeliac disease. The value of lipid screening in children with type 1 diabetes is unclear. Elevated cholesterol and/or triglycerides are commonly seen with poor glycaemic control.

Diabetes in adolescence

Teenage years are challenging – especially so for the teenager with diabetes. It is essential to have a non-judgemental approach that focuses on realistic shared goals. Threats of future complications are counterproductive and should be avoided. There needs to be effective preparation for adult life, including advice on sexual health, pregnancy and contraception, driving, employment, living away from home, alcohol and drugs. Eating disorders and depression are very common in older teenagers and require specialist input.

Good hand-over arrangements to the adult diabetes service are also essential, as many young people fall by the wayside at this stage.

Type 2 diabetes and MODY

Type 2 diabetes is increasingly evident in obese adolescents, particularly those from ethnic minorities. Management is aimed at weight control through healthy eating, exercise and the use of metformin to maximum tolerated doses. Other oral hypoglycaemic agents are added as necessary. Ultimately, all individuals with type 2 diabetes will required insulin therapy (on average after about 6–7 years).

Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes due to specific genetic defects of beta cell function, the commonest being mutations affecting hepatic nuclear factor 1α. MODY may present similarly to type 1 diabetes. It is dominantly inherited, therefore a parent is usually affected. Specific genetic tests are available. Treatment with a sulfonylurea such as glibenclamide is effective.

Secondary diabetes

Diabetes or glucose intolerance may occur secondarily to steroid excess, as in Cushing’s syndrome, or from high-dose steroid therapy.

The hypothalamus and pituitary

The hypothalamus and pituitary gland are together the principal command centre of the endocrine system. Pituitary hormones regulate metabolism (TSH), growth (growth hormone) and sexual development (follicle-stimulating hormone and luteinizing hormone – see ‘Sexual development’ later in the chapter), the adrenal gland (ACTH), water balance (antidiuretic hormone; see Chapter 11, p. 131) and lactation (prolactin and oxytocin). Structural lesions of the hypothalamus and pituitary include congenital malformations and tumours, e.g. craniopharyngioma (see Chapter 7, p. 74), and result in deficiency of some or all of the pituitary hormones – known as hypopituitarism.

The pituitary gland may be congenitally absent or hypoplastic. This may be associated with other midline congenital anomalies such as cleft palate. Congenital hypopituitarism of hypothalamic or pituitary origin may be associated with the development of neonatal hypoglycaemia and, less commonly, cholestatic jaundice secondary to neonatal hepatitis (see also Chapter 13, p. 175).

Cushing’s syndrome

Cushing’s syndrome in children is almost always iatrogenic. The principal clinical features are growth impairment, central obesity, moon face, buffalo hump, hypertension and glucose intolerance or frank diabetes. After iatrogenic steroid exposure, ACTH-secreting pituitary adenomas (Cushing’s disease) are the commonest cause of Cushing’s syndrome in childhood, albeit still very rare. Adrenocortical tumours may also cause Cushing’s syndrome. Investigation is aimed at confirming glucocorticoid excess and determining if it is ACTH-dependent. Imaging is then used to localize the lesion, preparatory to surgery.

Adrenal insufficiency

The adrenal glands, named for their position at the superior pole of each kidney, comprise an inner medulla and an outer cortex. The medulla secretes the vasoactive catecholamines adrenaline (epinephrine), noradrenaline (norepinephrine) and dopamine. The adrenal cortex secretes the steroids cortisol and aldosterone and a modest quantity of androgens. Cortisol production is stimulated by the pituitary hormone, adrenocorticotrophic hormone (ACTH).

Cortisol is essential for survival and has diverse effects on metabolism, immunity and cardiovascular and renal function. These effects are most apparent as mediators of the body’s response to stress, such as illness, through its ability to mobilize glucose stores, improve myocardial and skeletal muscle contractility, and to enhance the pressor action of catecholamines.

Aldosterone has a key role in maintaining electrolyte balance and blood pressure by causing sodium retention and potassium excretion by the kidney. Retention of sodium leads to elevation of blood pressure.

Adrenal insufficiency most often occurs due to congenital adrenal hyperplasia (see p. 152) or secondary to hypopituitarism (as in Case 12.3). Primary adrenal insufficiency is extremely rare. It may be congenital, but it most commonly arises from autoimmune destruction of the adrenal gland, often in association with other autoimmune diseases, notably mucocutaneous candidiasis, hypoparathyroidism, hypothyroidism and diabetes mellitus (polyglandular endocrinopathy), in which case there is often a positive family history. It manifests with insidious malaise, weakness and weight loss and orthostatic hypotension. Hyperpigmentation may occur, classically affecting the buccal mucosa, scars and skin creases.

Case 12.3

A boy with adrenal insufficiency

Freddie, aged 7 years, was admitted with gastroenteritis. He had congenital hypopituitarism requiring multiple pituitary hormone replacement therapy. His oral hydrocortisone treatment was doubled, but the following morning he was found to be hypotensive and drowsy. His blood glucose was 2.9 mmol/L, and his serum sodium was 128 mmol/L. A diagnosis of adrenal crisis was made, and he was promptly treated with parenteral glucose, intravenous hydrocortisone and 20 mL/kg of normal saline. Within a few hours, he was much better.

Physiological steroid replacement with hydrocortisone is essential. This must be doubled or trebled with intercurrent illness, and in severe illness the parenteral route must be used. Failure to give adequate steroid therapy results in adrenal crisis, as in case 12.3, when the patient presents with refractory hypotension, hypoglycaemia, hyponatraemia and variable hyperkalaemia. Prompt treatment with intravenous fluids, glucose and hydrocortisone is essential.

Adrenal crisis may also occur with surgery or intercurrent illness in patients on chronic steroid therapy, or following abrupt cessation of high-dose steroid therapy. Patients at particular risk include those with asthma on high-dose inhaled steroids, notably fluticasone preparations, or those who have recently completed high-dose steroid therapy, such as children with leukaemia or inflammatory bowel disease.

Thyroid gland

The thyroid gland primarily secretes thyroxine (T₄) – a ubiquitous regulator of cell function. The active hormone, tri-iodothyronine (T₃), is created by de-iodination of thyroxine in target tissues. Thyroxine secretion is regulated by the hypothalamus and pituitary glands through secretion of thyrotrophin-releasing hormone and consequently thyroid-stimulating hormone (TSH). TSH secretion increases thyroxine production and may produce enlargement of the thyroid gland – goitre. Excess thyroxine inhibits TSH secretion. See Table 12.1 for the clinical assessment of thyroid function.

Table 12.1 Clinical assessment of thyroid function

	Congenital hypothyroidism	Congenital hyperthyroidism
Neonatal onset	Lethargy	Goitre
	Poor feeding	Low birth weight
	Prolonged jaundice	Irritability
	Coarse features	Tachycardia
	Hoarse cry	Tachypnoea
	Umbilical hernia	Hypertension
	Mental retardation	Failure to thrive
	Juvenile hypothyroidism	Graves’ disease
Childhood onset	Growth failure	Emotional lability
	Dry skin and hair	Insomnia
	Yellow pigmentation	Tremor
	(carotenaemia)	Voracious appetite
	Intellectual impairment	Goitre
	Goitre	Tachycardia
	Constipation	Muscle weakness
	Cold intolerance	Proptosis
	Early puberty (girls)

Thyrotoxicosis

Case 12.4

A girl with high metabolic rate

Anna, aged 12 years, presented with a 4-month history of weight loss despite a huge appetite. She had been more irritable of late and was not sleeping. She complained of a tremor. On examination she had warm hands and a tachycardia (100 beats per minute at rest). There was a marked tremor of her outstretched hands. She had an evident goitre with an easily heard vascular bruit.

Hyperthyroidism in older children – usually girls (as in Case 12.4) – is an autoimmune condition. These children make thyroid-stimulating antibodies, which mimic the action of TSH. Although Graves’ disease seems obvious it may be subtle. Irritability, poor exercise tolerance and some thyroid enlargement can be normal in adolescence. The weight loss may be ascribed to anorexia!

Hyperthyroidism is treated with anti-thyroid drugs such as carbimazole or propylthiouracil in combination with symptomatic relief with beta-blockers. A proportion of patients with Graves’ disease develop thyroid eye disease with exophthalmos. Such patients need joint management with an ophthalmologist. Eye protection such as patching, and use of artificial tears, is needed in the initial phase of management. The therapeutic goal is suppression of thyroxine synthesis. Two different therapeutic strategies may be employed: dose titration, in which the dose of carbimazole or propylthiouracil is adjusted to maintain thyroxine in the upper normal range, or ‘block and replace’ in which endogenous thyroxine synthesis is completely suppressed, and thyroxine is given to maintain the euthyroid state. If relapse occurs after cessation of maintenance therapy, then radioiodine therapy or thyroidectomy is normally undertaken. Most clinicians advise radio-iodine therapy as this avoids the risks of surgery and the cosmetic distress of a prominent neck scar. Radio-iodine is safe in children and adolescents. Nevertheless, some families prefer the option of surgery.

Neonatal thyrotoxicosis affects 1–2% of infants born to mothers with a history of autoimmune hyperthyroidism due to transplacental passage of maternal thyroid-stimulating antibodies. It is important to advise girls who have had Graves’ disease of the potential risk to future children, due to transplacental passage of thyroid receptor antibodies, so that the infant may be appropriately monitored.

Hypothyroidism

Congenital hypothyroidism is a relatively common disorder affecting about 1 in 3500 births. If undetected in early infancy, irreversible mental handicap results. The full syndrome, as described in Case 12.5, is rarely seen, as most developed countries have instituted screening for neonatal hypothyroidism. Occasionally, hypothyroidism detected at birth is temporary, but normally it is a life-long condition. If diagnosed promptly on screening, the progress for growth and intellectual development is good.

Case 12.5

A baby with slow metabolic rate

A 3-month-old baby, a refugee from Kosovo, presented with failure-to-thrive. The facial features were rather coarse and the skin was dry. The tongue tended to protrude and there was an umbilical hernia. There was a tinge of jaundice. The baby seemed apathetic and was not smiling or interacting with the carers. Blood testing showed a low thyroxine but very high TSH levels.

Hypothyroidism can also present later in childhood with growth failure, constipation, lethargy, dry skin and hair and poor school progress. Juvenile hypothyroidism is typically of gradual onset, and goitre is not readily evident. It is almost always an autoimmune disease and consequently more common in children with diabetes and coeliac disease. Hypothyroidism also occurs more commonly in children with chromosomal abnormalities, notably Down syndrome. Hypothyroidism is treated with thyroxine replacement.

Neonatal screening

The advent of neonatal screening for congenital hypothyroidism and phenylketonuria has allowed effective treatment for affected children. Treatment at an early stage is completely effective at preventing the poor neurodevelopmental outcomes seen in the past. In the UK, hard-to-reach groups such as travelling families, or newly arrived refugees, may slip through the net, and these diagnoses must be considered. Screening for cystic fibrosis, haemoglobinopathy and medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is also part of the neonatal screening test (see Chapter 17, p. 250).

Phenylketonuria

Phenylketonuria (PKU) is normally detected by the neonatal screening test, which is performed once a child is established on feeds at 5 to 9 days old. In Case 12.6, early treatment with dietary restriction of phenylalanine would have prevented its toxic effect on the brain, which is largely irreversible. PKU is caused by deficiency of phenylalanine hydroxylase, which prevents phenylalanine (an essential amino acid) being converted to tyrosine, and toxic metabolites accumulate.

Case 12.6

An infant with impaired metabolism

A travelling family attended clinic with their only child, Davie, who was 10 months old. They described episodes of arching his back with crying, as if distressed. He was not able to sit by himself or crawl and had blonde hair and blue eyes despite his parents’ dark hair. There was a musty smell to his urine and his head circumference was below the 0.4th centile. He had not been brought for his neonatal screening and was lost to follow-up. Phenylketonuria was suspected, and confirmed on plasma amino-acid analysis.

After diagnosis, dietary treatment with a very low protein diet is commenced. Small amounts of phenylalanine are required in the diet for normal growth and development, given as ‘exchanges’. Vitamin and mineral supplements are given to prevent micronutrient deficiencies. Monitoring of phenylalanine levels is used to adjust the number of exchanges. Poor compliance with diet leads to poor concentration, lethargy and deteriorating school performance.

Children born to mothers with PKU are at risk of mental retardation if the diet is not very strictly observed from before conception and throughout pregnancy (see Chapter 18, p. 265).

Growth

Paediatrics is practised against a moving baseline. Children grow and develop through fetal life, infancy, childhood and on into adolescence when the upheavals of puberty herald sexual maturity, after which linear growth ceases. This natural progression is one of the joys and fascinations of child health. ‘Has it affected growth?’ is an important question for any complaint – poor growth signifying significant constitutional disease.

History

As growth continues through childhood we need information about past growth to comment on any abnormality. It also helps to compare children with their peers and with other family members. ‘He is the smallest in his class’ tells us something. ‘He used to be average but now he’s the smallest’ tells us more. ‘She’s tiny, but her Mum is only 142 cm’ is useful, but remember that her mum may have an undiagnosed cause for her short stature. Parents often keep records of children’s height and weight, and any available past medical records should be reviewed. Ask about diet, especially if weight change is a concern. Make careful enquiries about any other symptoms. Perinatal events may impair long-term growth so collect information about conditions such as preterm delivery and low birth weight. Severe illnesses or impaired nutrition in early life may also impair growth.

Examination

Children’s growth can be conveniently compared with population norms using a growth chart. These show the average height for age and sex – the 50th centile – and other centiles above and below. Always plot the height and weight and, in young children, the head circumference and add any available historical measurements.

It is useful to consider parents’ heights; short but normal children usually have short parents. The mid-parental target height may be calculated by averaging the parents’ heights and either adding 7 cm for boys, or subtracting 7 cm for girls. The resultant value ± 8.5 cm (girls) or ± 10.0 cm (boys) is the target height ± 95% confidence interval.

Children’s growth potential is influenced by perinatal events and early illnesses.

Always perform a careful general examination, looking for any systemic disease that might cause growth failure.

Look at the body proportions. Are the arms and fingers unusually long or unusually short? Are there any dysmorphic features? Ask if the parents have difficulty obtaining clothes – this is a clue to unusual proportions.

Finally, remember that pituitary abnormalities might affect vision as well as growth or puberty. Test visual acuity (finger counting), pupil reactions, visual fields by confrontation, and ophthalmoscopy, looking in particular for the pale optic disc of optic atrophy. Remember that these clinical tests are rather crude. Accurate tests of visual acuity and visual field measurement should be considered.

Physical examination of progress through puberty demands careful recording of the extent of breast development, the nature and distribution of pubic hair, the volume of the testes and the development of the penis and scrotum. These examinations can be embarrassing for the adolescent and should be carried out by those competent to make a sensible assessment. Guidance on the staging of puberty is included on growth charts.

Investigations

Bone age

A radiograph of the non-dominant hand and wrist is compared with reference standards to give a bone age – the age equivalent to the degree of bone maturation.

Phases of growth

Growth may be conveniently considered as four phases: fetal, infant, childhood and adolescent. At each stage, optimal growth requires a normal capacity to grow, an unrestricted nutrient supply, appropriate hormonal stimuli and emotional well-being. To these, may be added the absence of significant constitutional illness.

Fetal growth

The fetus depends for its nutrition on the mother via the placenta. Maternal intake may be compromised by poor diet, by hyperemesis gravidarum, and by poor maternal health. Impaired placental function, as with maternal hypertension, will progressively compromise the fetus. Nutrient supply to the fetus may be limited by competition from other siblings in multiple pregnancy. The fetus itself may have a reduced capacity to grow, due to chromosomal disorders such as Down syndrome or other genetic anomalies such as skeletal dysplasia, or from congenital infection.

In the absence of maternal or fetal compromise, birth weight is primarily a reflection of the intrauterine environment, and may not correspond to the child’s growth potential after birth. The child with intrauterine growth retardation typically shows rapid ‘catch-up’ growth, whereas a big baby may show the reverse phenomenon – ‘catch-down’ growth. It is helpful to look at length and head circumference in deciding if such a growth pattern is abnormal. If development is normal, and a thorough physical examination is unrevealing, watchful waiting will normally suffice.

Intrauterine growth retardation

Poor maternal nutrition and impaired placental function exert progressive effects on the fetus as the nutrient requirement increases through pregnancy. Such infants show marked asymmetry at birth, with low birth weight but preservation of head circumference and, to a lesser extent, length – so called asymmetrical intrauterine growth restriction (IUGR). In contrast, fetal causes of growth impairment usually produce symmetrical IUGR.

Large birth weight (macrosomia)

In the mother with poorly controlled diabetes, there may be excessive nutrient supply to the fetus. Maternal hyperglycaemia results in compensatory fetal hyperinsulinism and excessive fetal growth. After birth, the fetus continues to secrete insulin to excess and is at risk of severe hypoglycaemia. More rarely, the fetus produces excessive fetal growth factors – as with Beckwith syndrome, resulting in excessive fetal growth and neonatal hypoglycaemia, associated with other congenital abnormalities.

Infant growth

After birth, growth in weight, length and head circumference is rapid. Impaired growth in infancy – failure-to-thrive, as in the fetus – may signify nutrient lack, impaired growth potential, underlying illness or emotional deprivation. Several factors may work in combination.

Faltering growth (failure-to-thrive)

Case 12.7

An infant who is failing to thrive

Michael was born to a 17-year-old mother after a concealed pregnancy. He was born significantly growth-retarded with a birth weight of 2.2 kg. He had persistent vomiting with feeds and poor weight gain and was admitted to hospital for investigation at 4 weeks of age weighing 2.4 kg. His feeding was observed, and it was noted that his mother did not appear to interact with him or respond to his crying until prompted by the nursing staff. She handled him roughly. She admitted to very mixed feelings about having a baby, and felt she was unable to cope with the responsibility. She appeared depressed.

Michael’s vomiting improved with a milk thickener, and his weight gain also improved. Michael temporarily went into the care of his maternal grandparents. His mother was advised to seek treatment for her depression, and parenting classes were arranged for her. Michael later returned to his mother’s care, where he continued to thrive.

Case 12.7 highlights the importance of a nurturing environment, and adequate food intake in infant growth. Hormone imbalance is very rare as a cause of faltering growth in infancy. Relevant considerations when seeing a baby with failure-to-thrive are:

• Is there an underlying pathological cause for growth failure, or is the baby constitutionally small?

• Does poor weight gain reflect poor food supply and intake or nutrient loss through vomiting?

• Could faltering growth reflect emotional neglect?

A careful history should suggest the cause of low birth weight. Physical examination and some investigations will determine if the baby is ill. An admission to observe the mother and child together, and to assess the baby’s food intake, can be useful. Maternal post-natal depression is common and needs appropriate management.

See Table 12.2 for the principal causes of failure-to-thrive.

Table 12.2 Principal causes of failure-to-thrive

Classification	Diagnosis	Investigation
Inadequate intake	Neglect Failure of breast-feeding Cleft palate	Observation
Vomiting	Gastrooesophageal reflux Pyloric stenosis	Observation, upper gastrointestinal barium study, abdominal ultrasound
Malabsorption	Cystic fibrosis, coeliac disease Milk intolerance	Sweat test Coeliac antibodies, upper small bowel biopsy Stool sugar chromatography, urine reducing substances, trial of alternative milk
Renal	Urinary tract infection	Urine culture
Cardiac	Congenital heart disease	Echocardiogram
Respiratory	Infection	Nasopharyngeal aspirate, chest X-ray
Constitutional	Chromosomal disorders Congenital syndromes Inborn errors of metabolism Perinatal infections	As appropriate

Growth in childhood

Short stature

For practical purposes in the UK, short stature is defined as height less than the 2nd centile; however, this definition includes 1 in 50 normal, healthy children. The 0.4th centile includes only 1 in 250 normal but short children, and the likelihood of an underlying pathological cause for short stature is much higher. An individual height measurement is a ‘snapshot’ of growth, and previous height measurements are extremely helpful. The child who has always been short is more likely to be normal, whereas the child who has shown poor growth and is crossing centiles should provoke concern, even if still within the normal range. Only a small number (<10%) of short children have an endocrine cause for short stature. See Table 12.3 for the causes of short stature.

Table 12.3 Causes of short stature

	Cause	Diagnostic factors
Constitutional		Parental heights Growth follows centile line
Emotional		History of deprivation Withdrawn or disturbed behaviour
Syndromes	Turner syndrome Achondroplasia Russell–Silver syndrome	Girls Dysmorphic features Delayed puberty Abnormal body proportions Short limbs Low birth weight Triangular facies
Loss of growth potential	IUGR Severe early illness	Low birth weight For example, extreme prematurity or malnutrition
Chronic illness		Evidence of the illness Remember the effect of steroids
Endocrine	Growth hormone deficiency	Growth crossing centile lines Obesity Dysmorphic features

Psychosocial growth failure

In contrast to organic causes of growth failure, the effects of emotional deprivation on growth are hard to define and to diagnose. Case 12.8 is fairly cut and dried but the diagnosis must always be considered.

In Case 12.9, the severity of the boy’s short stature, his physical characteristics and the history of neonatal hypoglycaemia were strongly suggestive of growth hormone deficiency, which was confirmed by a growth hormone test. Subsequently, an MRI scan showed an empty pituitary fossa due to congenital absence of the anterior pituitary. In these cases the posterior pituitary is often abnormally placed (ectopic).

Use of growth hormone in children

Growth hormone is available for treatment of short stature due to several causes. It must be administered by a daily subcutaneous injection, normally given at night. Side-effects are rare, but include headaches, arthralgia, oedema and benign intracranial hypertension.

Case 12.8

A short and underweight boy

Michael was referred at the age of 5 years, following an adoption medical, because he was short and underweight. He had been taken into local authority care a year previously, after concerns about physical and emotional abuse. On examination, he was reserved, and did not play with the toys in the consulting room, preferring to sit under a table. On examination his height and weight were in proportion, although he was small, and no physical abnormalities were found. Routine investigations were normal. A diagnosis of probable psychosocial growth failure was made and his growth observed. After adoption, his growth progressively improved, confirming the diagnosis.

Current indications for growth hormone treatment in the UK include:

• Growth hormone deficiency

• Turner syndrome (see Chapter 18, p. 278)

• Prepubertal children with chronic renal failure

• Short children >3 years, born small for gestational age

• Prader-Willi syndrome (see Chapter 18, p. 276).

• SHOX deficiency – the SHOX gene (short stature homeobox gene on X) is present on the X and Y chromosomes. Deficiency of SHOX contributes the majority of the growth failure seen in Turner’s syndrome. SHOX deficiency also occurs as an isolated condition due to genetic mutations affecting SHOX.

Case 12.9

A very small schoolboy

Kieran, aged 5 years, was noted to be extremely short at school entry. He was born by vaginal breech delivery after induction of labour at 38 weeks’ gestation. His birth weight was 3.06 kg. He was admitted to special care at 6 hours of age with hypoglycaemia which resolved with nasogastric tube feeding. Thereafter, he had put on weight satisfactorily, but had always been small and his 3-year-old brother was as tall as Kieran. On examination he had a prominent forehead with delicate facial features. His hands and feet were small and he was relatively fat.

Sexual development

Disorders of sexual development

The first phase of sexual development occurs in the fetus, with genetically determined male or female sexual differentiation occurring in early fetal life. Occasionally, this process is perturbed, resulting in disorders of sex development.

The birth of a child of uncertain sex is a harrowing experience for parents and presents a major diagnostic challenge. The fetus is programmed to develop as a female in the absence of masculinizing signals – testosterone and anti-müllerian hormone from the fetal testes. Accordingly, a genetically female infant will only have disorders of sexual development (DSD) following fetal androgen exposure – normally due to congenital adrenal hyperplasia (CAH).

DSD in a genetically male infant potentially has many causes, the commonest being androgen insensitivity. In 60% of males with DSD no cause is identified.

Diagnosis of the cause of DSD requires a systematic approach. Ambiguous genitalia may be associated with other congenital abnormalities, and these may point to the diagnosis. Physical examination may reveal palpable testes, indicating male DSD. An abdominal ultrasound will determine the presence or otherwise of the uterus and ovaries, and may show adrenal enlargement in CAH. Blood and urine tests for CAH should not be done before 72 hours of age as placental steroids will affect the result, making interpretation difficult or impossible.

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia is the commonest cause of impaired adrenal steroid secretion in childhood. This results from inborn errors affecting steroidogenic pathways – principally 21-hydroxylase, which accounts for over 95% of CAH. The inability to synthesize cortisol leads to hypersecretion of ACTH, which in turn produces adrenal hyperplasia. As 21-hydroxylase also mediates aldosterone synthesis, severe enzyme deficiency leads to loss of aldosterone also, and results in salt-losing CAH. The block in cortisol synthesis results in cortisol precursors being converted into androgens. The diagnosis is confirmed by the finding of elevated 17-alpha-hydroxyprogesterone (as in Case 12.10).

Case 12.10

A baby of indeterminate sex

A baby born after an uneventful pregnancy was found to have ambiguous genitalia. There was a small but distinct phallus. Doctors could not determine if there was labial fusion or an underdeveloped scrotum. There were no gonads palpable. Investigation revealed normal female chromosomes and normal vagina, uterus and ovaries on ultrasound. On the 8th day of life the baby’s potassium rose to 7.8 mmol/L, with a sodium of 129 mmol/L. The 17-alpha-hydroxyprogesterone level was raised, confirming salt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

In female infants, androgen exposure causes virilization with clitoral hypertrophy and variable fusion of the labia minora. The male infant with 21-hydroxylase deficiency appears normal, and commonly the first manifestation is with a salt-losing adrenal crisis, typically in the 2nd week of life. The baby may present in extremis with shock, hyponatraemia, hypoglycaemia and severe hyperkalaemia.

Once the diagnosis of CAH is made, hydrocortisone is used to replace cortisol, restoring negative feedback to the hypothalamus and pituitary. ACTH secretion falls to normal levels, switching off androgen production. Salt-losing children require mineralocorticoid replacement with fludrocortisone and, in infancy, additional sodium chloride.

Corrective surgery of the virilized female infant is complex, and presents significant ethical and practical dilemmas. In the first instance, examination under anaesthesia is required to delineate the perineal anatomy. Severe degrees of virilization result in the urethra entering the vagina in a common urogenital sinus. It is necessary to restore the normal position of the urethra to achieve continence in later life. Surgery is best performed in infancy, when excellent healing may be achieved. In the past, clitoral reduction surgery (‘cliteroplasty’) was also routinely performed, but this is purely a cosmetic procedure, and may result in loss of clitoral sensation, with detrimental sexual functioning in adult life. Accordingly, most surgeons prefer to defer clitoral reduction until the girl herself wishes to have it done, usually in the early teenage years. With severe degrees of virilization, where the clitoris has formed into a well-developed phallus, this is impractical, and early surgery is needed. Exposure to androgens also results in vaginal stenosis. In the past, it was routine to perform vaginoplasty in infancy, but this requires the daily use of vaginal dilators to prevent re-stenosis, which is painful and psychologically distressing to child and parents alike. Accordingly, vaginoplasty is normally deferred until the girl is in puberty, at which point endogenous oestrogen will normally greatly reduce re-stenosis, thus minimizing the need for use of dilators. The desire to delay corrective surgery may be at variance with the parents’ wishes. The parents often want a normal appearance to be achieved without delay, even when this may conflict with the advice of the medical team as to the child’s best interests.

The ongoing care of the girl and her family with CAH requires the input of a multi-disciplinary team, including an endocrinologist, urologist, clinical psychologist and specialist nurse. In the UK such services are based at specialist supra-regional centres.

Puberty

Puberty – the transition from childhood to sexual maturity – is a complex, hormonally regulated process. Gonadotrophin-releasing hormone (GnRH), secreted by the hypothalamus, stimulates secretion of the gonadotrophins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary. FSH acts on the ovary and testis to induce gametogenesis – the production of eggs or sperm – whilst LH stimulates oestrogen and testosterone production, respectively. Oestrogen and testosterone levels rise progressively as puberty progresses until attaining adult levels. Oestrogen and testosterone stimulate growth and development of secondary sexual characteristics. Oestrogen and testosterone are inter-convertible through the action of the enzyme aromatase, particularly found in adipose tissue – thus boys make small amounts of oestradiol, and girls make small amounts of testosterone and androstenedione. Through poorly understood mechanisms, the adrenal cortex also secretes androgens (adrenarche), contributing as much as 50% of total androgens in girls.

In girls, normal puberty is signalled by breast development known as thelarche, and is normally followed within 6–12 months by the appearance of pubic hair – pubarche. The attainment of fertility is signalled by the onset of menstruation – menarche. Onset of puberty in girls normally occurs between the ages of 9 and 13 years, with menarche occurring about 2 years later. Onset of puberty in girls is associated with rapid growth. After menarche, growth progressively declines until epiphyseal fusion marks the end of growth, typically about 18 months later.

In boys, puberty is signalled by testicular enlargement. Testicle size may be assessed with an orchidometer (see Figure 12.1). Puberty starts when testicular size reaches 4 mL, progressing through puberty to 15–25 mL in adulthood. In boys, puberty normally starts between 10 and 14 years. The first visible sign of puberty is the appearance of pubic hair, followed by growth of the penis. Testicular size of 12 mL is attained by mid-puberty, when nocturnal FSH secretion reaches adult levels. This corresponds both to the timing of the first ejaculation and the peak of the adolescent growth spurt. Growth continues until epiphyseal fusion occurs in the mid to late teens.

Figure 12.1 Orchidometer for assessment of testicular size in boys. The numbers indicate size in millilitres.

There are a number of normal variants of puberty:

1. Premature thelarche describes the appearance of breast tissue, sometimes unilateral, in female infants and young girls. The breast size fluctuates, and prolactin and oestrogen levels are in the normal prepubertal range. It remits spontaneously by 2 or 3 years of age.

2. Premature adrenarche is a result of the secretion of adrenal androgens by the adrenal cortex. It typically occurs in girls in mid childhood and may result in the development of body odour, acne, and axillary and pubic hair. Oestrogen levels are prepubertal. Measurement of the exclusive adrenal androgen dehydroepiandrosterone or its sulphate confirms the diagnosis.

3. Gynaecomastia is breast development in boys. It occurs to some degree in all boys in early to mid puberty, but may be pronounced, particularly in obese boys. Where gynaecomastia leads to social difficulties, such as severe embarrassment or school refusal, surgery may be appropriate.

Precocious puberty

When puberty occurs before 8 years in girls or 9 years in boys, it is said to be precocious. Normal, but early puberty is described as central precocious puberty, whereas puberty arising from autonomous oestrogen or androgen secretion is described as gonadotrophin-independent precocious puberty.

Case 12.11

A girl with precocious puberty

Katie presented with rapid growth, breast development and pubic hair at the age of 4 years. She had spastic diplegic cerebral palsy secondary to hydrocephalus and prematurity at birth. Investigation showed elevated gonadotrophins and oestradiol, confirming central precocious puberty. Her hydrocephalus was felt to be the likely cause. MRI scan confirmed that her hydrocephalus was stable, and showed no other abnormality.

In central precocious puberty, as in Case 12.11, gonadotrophin levels are elevated to pubertal levels, with elevated oestrogen or testosterone. Central precocious puberty is relatively common in girls, and is usually idiopathic, but in a small number there is an underlying cause such as a hypothalamic hamartoma or hydrocephalus. In contrast, central precocious puberty in boys is nearly always abnormal. Severe hypothyroidism may cause precocious puberty in girls, but unlike other causes of early puberty, there is no accompanying growth spurt. In boys, testicular enlargement, but not true puberty, is seen.

Gonadotrophin-independent precocious puberty is always abnormal; gonadotrophins are suppressed, or even undetectable with high oestrogen or androgens. In boys, testicular examination reveals prepubertal testes (<4 mL), or unilateral enlargement associated with a functional testicular tumour. If the testes are small, an androgen-secreting tumour, usually adrenal, or previously undiagnosed CAH, are the most likely causes. Some boys have familial, male-limited precocious puberty due to activating mutations of the LH receptor – testotoxicosis.

In girls, ovarian ultrasound will usually show unilateral ovarian enlargement, either from a functional ovarian tumour or McCune–Albright syndrome. In girls with McCune–Albright syndrome, gonadotrophin-independent precocious puberty is common due to an activating mutation affecting a number of endocrine and other systems.

Girls with androgen excess from CAH or androgen-secreting tumours show virilization – excessive development of facial and body hair with clitoral enlargement and other symptoms such as deepening of the voice or frontal recession.

Some tumours such as hepatoblastomas and teratomas may secrete human chorionic gonadotrophin (hCG), thus inducing gonadotrophin-independent precocious puberty. hCG and alpha-fetoprotein are markedly elevated.

The great majority of children with precocious puberty are girls in mid-to-late childhood with idiopathic central precocious puberty. Precocious puberty after age 7 is unlikely to affect final adult height, and is not physically harmful. Accordingly, the main indication for treatment is behavioural or emotional problems associated with sexual development.

Treatment of central precocious puberty is with GnRH super-analogues, which, after initial stimulation of the pituitary, down-regulate gonadotrophin secretion and thus switch off oestrogen or testosterone synthesis. Treatment of gonadotrophin-independent precocious puberty is directed towards treating the underlying cause, if possible, and using specific inhibitors of sex hormone synthesis and/or action.