Molecular mimicry probably occurs between an environmental trigger and an antigen on the surface of β-cells of the pancreas. Triggers which may contribute are enteroviral infections, accounting for the more frequent presentation in spring and autumn, and diet, possibly cow’s milk proteins (Fig. 25.1) and overnutrition. In genetically predisposed individuals, this results in an autoimmune process which damages the pancreatic β-cells and leads to increasing insulin deficiency. Markers of β-cell destruction include islet cell antibodies and antibodies to glutamic acid decarboxylase (GAD), the islet cells and insulin. There is an association with other autoimmune disorders such as hypothyroidism, Addison disease, coeliac disease and rheumatoid arthritis in the patient or family history.

Figure 25.1 Stages in the development of diabetes.

Box 25.3 The diabetes team

• Consultant paediatrician(s) with a special interest in diabetes

• Paediatric diabetes specialist nurse(s)

• Paediatric dietician

• Clinical psychologist

• Social worker

• Adult diabetologist for joint adolescent clinics

• Parent/patient support groups.

The initial management will depend on the child’s clinical condition. Those in advanced diabetic ketoacidosis require urgent hospital admission and treatment (see below). Most newly presenting children are alert and able to eat and drink and can be managed with subcutaneous insulin alone. Intravenous fluid is required if the child is vomiting or dehydrated. In most centres with sufficient resources, children newly presenting with diabetes who do not require intravenous therapy are not admitted to hospital but are managed entirely at home.

An intensive educational programme is needed for the parents and child, which covers:

• A basic understanding of the pathophysiology of diabetes

• Injection of insulin: technique and sites

• Diet: reduced refined carbohydrate; healthy diet with no more than 30% fat intake; ‘carbohydrate counting’, estimating the amount of carbohydrate in food to allow calculation of the insulin required for each meal or snack

• Adjustments of diet and insulin for exercise

• ‘Sick-day rules’ during illness to prevent ketoacidosis

• Blood glucose (finger prick) monitoring and blood ketones when unwell

• The recognition and staged treatment of hypoglycaemia

• Where to get advice 24 hours a day

• The help available from voluntary groups, e.g. local groups or ‘Diabetes UK’

• The psychological impact of a lifelong condition with potentially serious short- and long-term complications.

A considerable period of time needs to be spent with the family to provide this information and psychological support. The information provided for the child must be appropriate for age, and updated regularly. The specialist nurse should liaise with the school (teachers, those who prepare school meals, physical education teachers) and the primary care team.

Insulin

Insulin is made chemically identical to human insulin by recombinant DNA technology or by chemical modification of pork insulin. All insulin that is used in the UK in children is human and in concentrations of 100 U/ml (U-100). The types of insulin include:

• Human insulin analogues. Rapid-acting insulin analogues, e.g. insulin lispro, insulin glulisine or insulin aspart (trade names Humalog, Apidra and NovoRapid, respectively) – with a much faster onset and shorter duration of action than soluble regular insulin. There are also very long-acting insulin analogues, e.g. insulin detemir (Levemir) or glargine (Lantus)

• ‘Short-acting’ soluble human regular insulin. Onset of action (30–60 min), peak 2–4 h, duration up to 8 h. Given 15–30 min before meals. Trade named examples are Actrapid and Humulin S

• Intermediate-acting insulin. Onset 1–2 h, peak 4–12 h. Isophane insulin is insulin with protamine, e.g. Insulatard and Humulin I

• Predetermined preparations of mixed short- and intermediate-acting insulins with 25% or 30% rapid-acting components.

Insulin can be given by continuous infusion of rapid-acting insulin from a pump or by injections using a variety of syringe and needle sizes, pen-like devices with insulin-containing cartridges, and jet injectors that inject insulin needle-free as a fine stream into the subcutaneous tissue.

Insulin may be injected into the subcutaneous tissue of the upper arm, the anterior and lateral aspects of the thigh, the buttocks and the abdomen. Rotation of the injection sites is essential to prevent lipohypertrophy or, more rarely, lipoatrophy. The skin should be pinched up and the insulin injected at a 45° angle. Using a long needle or an injection technique that is ‘too vertical’ causes a painful, bruised intramuscular injection. Shallow intradermal injections can also cause scarring and should be avoided.

Most children are started on an insulin pump or a 3–4 times/day injection regimen (‘basal-bolus’) with short-acting insulin (e.g. Lispro, Glulisine or Insulin Aspart) being given (bolus) before each meal and snack plus long-acting insulin (e.g. Glargine or Detemir) in the late evening and/or before breakfast to provide insulin background (basal). These treatments both allow greater flexibility by relating the insulin more closely to food intake and exercise (Fig. 25.3). Patients and families are also taught how to correct any sugar above 10 mmol/L between usual meal times by extra short-acting insulin injections. However, the input required by the teams to start these intensive regimens is high, as is the need for a supportive school environment, and some patients and families still rely on twice-daily treatment with premixed insulin.

Figure 25.3 Basal-bolus insulin regimen and continuous pump insulin regimen, showing the basal levels of insulin programmed into the pump (blue bars) and the bolus insulin (red pulses) given before each meal/snack according to carbohydrate intake.

Shortly after presentation, when some pancreatic function is preserved, insulin requirements often become minimal, the so-called ‘honeymoon period’. Requirements subsequently increase to 0.5–1 U/kg or even up to 2 U/kg per day during puberty.

Summary

Figure 25.6 Lipohypertrophy from insulin injections. (a) Injection sites. (b) Lipohypertrophy (arrow) from insulin injections.

The diet and insulin regimen need to be matched (Fig. 25.4). The aim is to optimise metabolic control while maintaining normal growth. A healthy diet is recommended, with a high complex carbohydrate and relatively low fat content (<30% of total calories). The diet should be high in fibre, which will provide a sustained release of glucose, rather than refined carbohydrate, which causes rapid swings in glucose levels. ‘Carbohydrate counting’ allows patients to calculate their likely insulin requirements once their food choice for a meal is known, and taking into account their pre-meal sugar level and post-meal exercise pattern. Learning this balancing act requires a lot of educational input followed by refinement in the light of experience.

Figure 25.4 Factors affecting blood glucose levels.

Blood glucose monitoring

Regular blood glucose profiles and blood glucose measurements, when a low or high level is suspected, are required to adjust the insulin regimen and learn how changes in lifestyle, food and exercise affect control. A record should be kept in a diary or transferred from the memory of the blood glucose meter. The aim is to maintain blood glucose as near to normal (4–6 mmol/L) as possible. In practice, in order also to avoid hypoglycaemic episodes, this means levels of 4–10 mmol/L in children and 4–8 mmol/L in adolescents for as much of the time as possible. Realistic goals need to be agreed, with compromises reached about the frequency of monitoring and lifestyle issues, especially in teenagers. During changes in routine (e.g. holidays) or illness, it is not unreasonable to ask for four or more tests per day. In reality, many adolescents test less than once per week, if at all.

Continuous glucose monitoring sensors (CGMS), using subcutaneous or transcutaneous sensors to provide a continuous reading of blood glucose, are now widely available, and refinement is underway to allow these devices to help control the insulin delivered from a pump, or to suggest doses for a given meal composition and size. Continuous glucose monitoring sensors also allow the detection of unexpected asymptomatic episodes of nocturnal hypoglycaemia or times of poor control during the day. Blood ketone testing (often using the same meter as for blood glucose) is mandatory during infections or when control is poor to try to avoid severe ketoacidosis. Urine ketone testing is still used in some centres.

The measurement of glycosylated haemoglobin (HbA_1c) is particularly helpful as a guide of overall control over the previous 6–12 weeks and should be checked at least 3 times per year. The level is related to the risk of later complications in a non-linear fashion, such that the risk of complications increases more rapidly with higher levels, but may be misleading if the red blood cell lifespan is reduced, such as in sickle cell trait or if the HbA molecule is abnormal, as in thalassaemia. Since 2009, the units of HbA_1c (originally expressed as a % figure) have been changed to an international reporting standard of mmol/mol. Until 2012, results will be reported in both old and new units to give everyone time to become familiar with the new units. A level of ≤58 mmol/mol (7.5%) is seen as an ideal target for patients, but in practice is only achieved in 50% or less of a clinic population in the UK.

Hypoglycaemia

Most children develop well-defined symptoms when their blood glucose falls below about 4 mmol/L. The symptoms are highly individual and change with age, but most complain of hunger, tummy ache, sweatiness, feeling faint or dizzy or of a ‘wobbly feeling’ in their legs. If unrecognised or untreated, hypoglycaemia may progress to seizures and coma. Parents can often detect hypoglycaemia in young children by their pallor and irritability, sometimes presenting as unreasonable behaviour. If there is any doubt, the blood glucose concentration should be checked or food given.

Treating a ‘hypo’ at an early stage requires the administration of easily absorbed glucose in the form of glucose tablets (e.g. Lucozade tablets or similar) or a non-diet sugary drink. Children should always have easy access to their hypo remedy, although young children quickly learn to complain of hypo-symptoms in order to leave class or obtain a sweet drink! Oral glucose gels (e.g. Glucogel) are easily and quickly absorbed from the buccal mucosa and so are helpful if the child is unwilling or unable to cooperate to eat. It can be administered by teachers or other helpers. Parents and school should be provided with a glucagon injection kit for the treatment of severe hypoglycaemia, and taught how to administer it intramuscularly to terminate severe hypos. After treatment of ‘hypos’, parents or carers should give the child some food (usually a biscuit or sandwich) to ensure the blood glucose does not drop again.

Severe hypoglycaemia can usually be predicted (or explained in retrospect – missed meal, heavy exercise). The aim is anticipation and prevention. Hypoglycaemia in an unconscious child brought to hospital is treated with glucose given intravenously.

Diabetic ketoacidosis

Presentation is described in Box 25.2, essential investigations in Box 25.4 and management in Figure 25.5.

Long-term management

The aims of long-term management are:

• Normal growth and development

• Maintaining as normal a home and school life as possible

• Good diabetic control through knowledge and good technique

• Encouraging children to become self-reliant, but with adult supervision until they are able to take responsibility

• Avoidance of hypoglycaemia

• The prevention of long-term complications and an HbA_1c of 58 mmol/mol (7.5%) or less.

These aims are difficult to achieve in all patients at all stages of their condition.

Problems in diabetic control

Good blood glucose control is particularly difficult in the following circumstances:

• Eating too many sugary foods, such as sweets taken at odd times, at parties or on the way home from school

• Infrequent or unreliable blood glucose testing. ‘Perfect’ results are often invented and written down just before clinic to please the diabetes team

• Illness – viral illnesses are common in the young and although it is usually stated that infections cause insulin requirements to increase, in practice the insulin dose required is variable, partly because of reduced food intake. The dose of insulin should be adjusted according to regular blood glucose monitoring. Insulin must be continued during times of illness and the urine or blood tested for ketones. If ketosis is increasing along with a rising blood sugar, the family should know how to seek immediate advice to ensure that they increase the soluble insulin dose appropriately or seek medical help for possible intravenous therapy

• Exercise – vigorous or prolonged planned exercise (cross-country running, long-distance hiking, skiing) requires reduction of the insulin dose and increase in dietary intake. Late hypoglycaemia may occur during the night or even the next day, but may be avoided by taking an extra bedtime snack, including slow-acting carbohydrate such as cereal or bread. Less vigorous exercise such as sports lessons in school and spontaneous outdoor play can be managed with an extra snack or a reduction in short-acting insulin before the exercise

• Eating disorders, which are common in young females with diabetes.

• Family disturbance such as divorce or separation

• Inadequate family motivation, support or understanding. As children can never have a ‘holiday’ from their diabetes, they need a great deal of encouragement to continuously maintain good control. Educational programmes for children and families need to be arranged regularly and matched to their current level of education. Special courses and holiday camps are available; in the UK they are organised by Diabetes UK and local groups.

Management at school

An individualised care plan should be developed by the parents, diabetes team and the school to address the specific needs of the child. This will include the child’s dietary needs, requirements to have snacks at specified times and what to do if the child becomes hypoglycaemic or loses consciousness. For younger children, support is needed to help calculate and give the pre-lunch insulin injection or bolus from the pump.

Puberty and adolescence

The rapid growth spurt in early puberty is governed by a complex interaction of hormonal changes, some of which involve insulin and insulin-like growth factors. Growth hormone, oestrogen and testosterone all antagonise insulin action and there is thus an increase in the insulin requirement from the usual 0.5–1.0 U/kg per day of early childhood up to ≥2 U/kg per day. The increase may be especially marked first thing in the morning. The psychological changes accompanying adolescence may make this a time of rebellion where adherence to insulin and dietary regimens is minimal. Diabetic teenagers know that they will not become ill immediately if they cheat with their diet or miss an injection. Some will inevitably test the degree to which the rules can be broken, choosing to ignore the uncomfortable facts of diabetes provided that they ‘feel OK’. This usually results in avoidance of blood testing and a tendency to work on the false assumption that feeling well equates with good control. Many teenage girls experiment with crash diets at some time, which are likely to cause major problems in diabetic control. They also learn that glycosuria can be used as an ‘aid’ to losing weight.

Battles with parents may concentrate on diabetic management instead of the more usual teenage concerns (Table 25.1). Conflict may also extend to involve the professionals of the diabetic team, because of intense anger against the disease which marks them out as different from their peers. Many parents are very protective at this time, whereas teenagers should be encouraged to take responsibility for their diabetes. Health education about smoking, alcohol and contraception may need to be provided. Liaison with a psychologist or child psychiatrist may be helpful. The professionals of the diabetic team may need to encourage diabetic teenagers to take better care of themselves. It is usually unhelpful to give lectures about the long-term risks to health, as these are likely to be seen as irrelevant by the teenagers. However, they may be helped if:

Table 25.1

How diabetes interferes with normal adolescence

Normal adolescence	How diabetes interferes
Physical and sexual maturation	Delayed sexual maturation
Physical and sexual maturation	Invasion of privacy with frequent medical examinations
Conformity with peer group	Meals must be eaten on time
Conformity with peer group	Frequent injections and blood tests
Self-image	Hypoglycaemic attacks show that they are different
Self-esteem	Impaired body image
Independence from parents	Parental over-protection and reluctance to allow their child to be away from home
Independence from parents	Battles over diabetes
Economic independence	Loading of insurance premiums
	Discrimination by employers
	Statutory rules against becoming a pilot or driving heavy goods or public service vehicles

• There are clear short-term goals agreed by the patient

• Their efforts to improve their diabetic control, e.g. an improving or satisfactory HbA_1c level, are communicated promptly and enthusiastically

• There is a united team approach, with agreement between professionals of the essentials they wish to promote and clear, unambiguous guidelines for health and diabetic management

• Peer group pressure is used to promote health. Activities such as holidays, etc., that allow teenagers to participate while learning about their diabetic management are encouraged. They may also benefit by being used as teachers of younger children.

Successful long-term diabetic management depends on education and increasing self-reliance and responsibility.

After many years in a children’s clinic, it can be difficult for the patient and family to move to the adult care environment. This transition is helped by discussing and planning the move well ahead of the time, and by the provision of joint clinics with the adult diabetologists through to the early twenties or end of tertiary education. Special peri-conceptional clinics have been established in some centres to help achieve near-ideal control before conception in planned pregnancies. Conception of a fetus with a high HbA_1c increases the risks of congenital abnormalities in the offspring.

Prevention of long-term complications

It has been shown that meticulous diabetic control delays or prevents diabetic retinopathy and nephropathy and, if retinopathy occurs, it can slow the progression. There is also evidence that good early control reduces the risk of later complications, even if control deteriorates later in life. Levels of glycosylated haemoglobin above 58 mmol/mol (7.5%) are related to the risk of later complications in an almost exponential fashion, and so the ideal is to aim for below this level as much as possible.

Although long-term health problems are uncommon during childhood, there needs to be regular review for long-term complications and associated illnesses:

• Growth and pubertal development. Some delay in the onset of puberty may occur. Obesity is common, especially in females, if their insulin dose is not reduced towards the end of puberty. Intensive insulin regimens increase the risk of excessive weight gain and BMI should be plotted at each clinic visit

• Blood pressure – must be checked at least once a year for evidence of hypertension

• Renal disease – the detection of microalbuminuria is an early sign of nephropathy and should be screened annually in teenagers

• Eyes – retinopathy or cataracts requiring treatment are rare in children but should be monitored annually after 5 years of diabetes or from the onset of puberty, ideally with retinal photography

• Feet – children should be encouraged to take good care of their feet from an early age, to avoid tight shoes and treat any infections early

• Other associated illnesses – coeliac disease and thyroid disease are more common in type 1 diabetes and easily missed clinically, so screening for them is recommended at diagnosis and subsequently (thyroid function yearly post-diagnosis and coeliac screening by tissue transglutaminase levels after 3 years) or if suspected clinically. There should be a low threshold for investigating for other autoimmune disorders (rheumatoid, vitiligo, etc.).

Hypoglycaemia

Hypoglycaemia is a common problem in neonates during the first few days of life (see Chapter 10). Thereafter, it is uncommon in non-diabetics. It is often defined as a plasma glucose <2.6 mmol/L, although the development of clinical features will depend on whether other energy substrates can be utilised. Clinical features include:

• Sweating

• Pallor

• Central nervous system signs of irritability, headache, seizures and coma.

The neurological sequelae may be permanent if hypoglycaemia persists and include epilepsy, severe learning difficulties and microcephaly. This risk is greatest in early childhood during the period of most rapid brain growth.

Infants have high energy requirements and relatively poor reserves of glucose from gluconeogenesis and glycogenesis. They are at risk of hypoglycaemia with fasting. Infants should never be starved for more than 4 h, e.g. preoperatively. A blood glucose should be checked in any child who:

• becomes septicaemic or appears seriously ill. ABC then DEFG – ‘Don’t Ever Forget Glucose’

• has a prolonged seizure

• develops an altered state of consciousness.

This is often done at the bedside, using glucose-sensitive strips, the accuracy of which is improved by use of a meter. However, the strips only indicate that the glucose is within a low range of values and any low reading must always be confirmed by laboratory measurement.

If the cause of the hypoglycaemia is unknown, it is vital that blood is collected at the time of the hypoglycaemia and the first available urine sent for analysis, so that a valuable opportunity for making the diagnosis is not missed (Box 25.5).

Causes

These are listed in Box 25.6.

Box 25.6 Causes of hypoglycaemia beyond the immediate neonatal period

Fasting

• Insulin excess

– Excess exogenous insulin, e.g. in diabetes mellitus/insulin given surreptitiously

– β-cell tumours/disorders – persistent hypoglycaemic hyperinsulinism of infancy (PHHI, previously called nesidioblastosis), insulinoma

– Drug-induced (sulphonylurea)

– Autoimmune (insulin receptor antibodies)

– Beckwith syndrome

• Without hyperinsulinaemia

– Liver disease

– Ketotic hypoglycaemia of childhood

– Inborn errors of metabolism, e.g. glycogen storage disorders

– Hormonal deficiency: GH↓, ACTH↓, Addison disease, congenital adrenal hyperplasia

Reactive/non-fasting

• Galactosaemia

• Leucine sensitivity

• Fructose intolerance

• Maternal diabetes

• Hormonal deficiency

• Aspirin/alcohol poisoning.

Ketotic hypoglycaemia is a poorly-defined entity in which young children readily become hypoglycaemic following a short period of starvation, probably due to limited reserves for gluconeogenesis. The child is often short and thin and the insulin levels are low. Regular snacks and extra glucose drinks when ill will usually prevent hypoglycaemia. The condition resolves spontaneously in later life. A number of rare endocrine and metabolic disorders may present with hypoglycaemia at almost any age in childhood. Hepatomegaly would suggest the possibility of an inherited glycogen storage disorder, in which hypoglycaemia can be profound.

Transient neonatal hypoglycaemia in neonates may be due to exposure to high levels of insulin in utero if mothers are diabetic or glucose intolerant. In contrast, recurrent, severe neonatal hypoglycaemia may be caused by persistent hypoglycaemic hyperinsulinism of infancy (PHHI, formerly called ‘nesidioblastosis’). This is a rare disorder of infancy where there are gene mutations of various pathways leading to dysregulation of insulin release by the islet cells of the pancreas leading to profound non-ketotic hypoglycaemia. Treatment with high-concentration dextrose solutions and diazoxide (plus other medications) may be required to maintain safe blood sugar levels pending investigation. Special scans reveal that up to 40% of cases are caused by localised lesions in the pancreas amenable to partial resection, although the majority of cases either require long-term medication or total pancreatectomy with the attendant risk of diabetes and exocrine pancreatic insufficiency.

Treatment

Hypoglycaemia can usually be corrected with an intravenous infusion of glucose (2 ml/kg of 10% dextrose followed by 10% dextrose infusion). Care must be taken to avoid giving an excess volume as the solution is hypertonic and could cause cerebral oedema. If there is delay in establishing an infusion or failure to respond, glucagon is given intramuscularly (0.5–1 mg). If a higher concentration than a 10% solution is required in a neonate, the low sugar is highly likely to be secondary to hyperinsulinism.

Corticosteroids may also be used if there is a possibility of hypopituitarism or hypoadrenalism. The correction of hypoglycaemia must always be documented with satisfactory laboratory glucose measurements.

Summary

Hypoglycaemia

• Should be excluded in any child with septicaemia, who is seriously ill, has a prolonged seizure or altered state of consciousness (‘Don’t Ever Forget Glucose’)

• Low blood glucose on bedside testing must be confirmed by laboratory measurement

• If the cause is unknown, diagnostic blood and urine samples should, if possible, be taken at the time.

Hypothyroidism

There is only a small amount of thyroxine transfer from the mother to the fetus, although severe maternal hypothyroidism can affect the developing brain. The fetal thyroid predominantly produces ‘reverse T₃’, a derivative of T₃ which is largely inactive. After birth, there is a surge in the level of thyroid-stimulating hormone (TSH) which is accompanied by a marked rise in T₄ and T₃ levels. The TSH declines to the normal adult range within a week. Preterm infants may have very low levels of T₄ for the first few weeks of life, while the TSH is within the normal range; under these circumstances, additional thyroxine is not required.

Congenital hypothyroidism

Detection of congenital hypothyroidism is important, as it is:

• Relatively common, occurring in 1 in 4000 births

• One of the few preventable causes of severe learning difficulties.

Causes of congenital hypothyroidism are:

• Maldescent of the thyroid and athyrosis – the commonest cause of sporadic congenital hypothyroidism. In early fetal life, the thyroid migrates from a position at the base of the tongue (sublingual) to its normal site below the larynx. The thyroid may fail to develop completely or partially. In maldescent, the thyroid remains as a lingual mass or a unilobular small gland. The reason for this failure of formation or migration is not well understood

• Dyshormonogenesis, an inborn error of thyroid hormone synthesis, in about 5–10% of cases, although commoner in some ethnic groups with consanguineous marriage

• Iodine deficiency, the commonest cause of congenital hypothyroidism worldwide but rare in the UK. It can be prevented by iodination of salt in the diet

• Hypothyroidism due to TSH deficiency – isolated TSH deficiency is rare (<1% of cases) and is usually associated with panhypopituitarism, which usually manifests with growth hormone, gonadotrophin and ACTH deficiency leading to hypoglycaemia or micropenis and undescended testes in affected boys before the hypothyroidism becomes evident.

The clinical features (Box 25.7 and Fig. 25.7) are difficult to differentiate from normal in the first month of life, but become more prominent with age. There is a slight excess of other congenital abnormalities, especially heart defects.

Box 25.7 Clinical features of hypothyroidism

Congenital	Acquired
Usually asymptomatic and picked up on screening. Otherwise:	Females > males Short stature/growth failure Cold intolerance Dry skin Cold peripheries Bradycardia Thin, dry hair Pale, puffy eyes with loss of eyebrows Goitre Slow-relaxing reflexes Constipation Delayed puberty Obesity Slipped upper femoral epiphysis Deterioration in school work Learning difficulties

Pale, cold, mottled dry skin

Coarse facies

Large tongue

Hoarse cry

Goitre (occasionally)

Umbilical hernia

Delayed development

Figure 25.7 Untreated congenital hypothyroidism.

Most infants with congenital hypothyroidism are detected on routine neonatal biochemical screening (Guthrie test), performed on all newborn infants, by identifying a raised TSH in the blood. However, thyroid dysfunction secondary to pituitary abnormalities may not be picked up at neonatal screening as they will have a low TSH. In some countries T₄ is also measured. Treatment with thyroxine is started at 2–3 weeks of age.

Early treatment of congenital hypothyroidism is essential to prevent learning difficulties. With neonatal screening, the results of long-term intellectual development have been satisfactory and intelligence should be in the normal range for the majority of children. Treatment is lifelong with oral replacement of thyroxine, titrating the dose to maintain normal growth, TSH and T₄ levels.

Juvenile hypothyroidism

This is usually caused by autoimmune thyroiditis. There is an increased risk in children with Down or Turner syndrome and of developing other autoimmune disorders, e.g. vitiligo, rheumatoid arthritis, diabetes mellitus. In some families, Addison disease may also occur.

The clinical features are listed in Box 25.7. It is commoner in females. There is growth failure accompanied by delayed bone age. Goitre is often present but this may also be physiological in pubertal girls. Treatment is with thyroxine.

Summary

Congenital hypothyroidism

• Is identified on routine neonatal biochemical screening (Guthrie test)

• Although present antenatally, treatment started soon after birth results in satisfactory intellectual development.

Hyperthyroidism

This usually results from Graves disease (autoimmune thyroiditis), secondary to the production of thyroid-stimulating immunoglobulins (TSIs). The clinical features are similar to those in adults, although eye signs are less common (Box 25.8 and Fig. 25.8). It is most often seen in teenage girls. The levels of thyroxine (T₄) and/or tri-iodothyronine (T₃) are elevated and TSH levels are suppressed to very low levels. Antithyroid peroxisomal antibodies may also be present which may eventually result in spontaneous resolution of the thyrotoxicosis but subsequently cause hypothyroidism (so-called hashitoxicosis).

Box 25.8 Clinical features of hyperthyroidism

Systemic	Eye signs (uncommon in children)
Anxiety, restlessness	Exophthalmos
Increased appetite	Ophthalmoplegia
Sweating	Lid retraction
Diarrhoea	Lid lag
Weight loss
Rapid growth in height
Advanced bone maturity
Tremor
Tachycardia, wide pulse pressure
Warm, vasodilated peripheries
Goitre (bruit)
Learning difficulties/behaviour problems
Psychosis

Figure 25.8 Exophthalmos in Graves disease.

The first-line of treatment is medical, with drugs such as carbimazole or propylthiouracil that interfere with thyroid hormone synthesis. Initially, β-blockers can be added for symptomatic relief of anxiety, tremor and tachycardia. There is a risk of neutropenia from anti-thyroid medication and all families should be warned to seek urgent help and a blood count if sore throat and high fever occur on starting treatment. Medical treatment is given for about 2 years, which should control the thyrotoxicosis, but the eye signs may not resolve. When medical treatment is stopped, 40–75% relapse. A second course of drugs may then be given or surgery in the form of subtotal thyroidectomy will usually result in permanent remission. Radioiodine treatment is simple and is no longer considered to result in later neoplasia. Follow-up is always required as thyroxine replacement is often needed for subsequent hypothyroidism.

Neonatal hyperthyroidism may occur in infants of mothers with Graves disease from the transplacental transfer of TSIs. Treatment is required as it is potentially fatal, but it resolves spontaneously with time.

Parathyroid disorders

Parathyroid hormone (PTH) promotes bone formation via bone-forming cells (osteoblasts). However, when calcium levels are low, PTH promotes bone resorption via osteoclasts, increases renal uptake of calcium and activates metabolism of vitamin D to promote gut absorption of calcium. In hypoparathyroidism, which is rare in childhood, in addition to a low serum calcium, there is a raised serum phosphate and a normal alkaline phosphatase. The parathyroid hormone level is very low. Severe hypocalcaemia leads to muscle spasm, fits, stridor and diarrhoea. It is a common problem in premature infants, and increasingly seen as a presentation of severe rickets (see Ch. 12). Other causes are rare in childhood.

Hypoparathyroidism in infants is usually due to a congenital deficiency (DiGeorge syndrome), associated with thymic aplasia, defective immunity, cardiac defects and facial abnormalities. In older children, hypoparathyroidism is usually an autoimmune disorder associated with Addison disease.

In pseudohypoparathyroidism there is end-organ resistance to the action of parathyroid hormone caused by a mutation in a signalling molecule. Serum calcium and phosphate levels are abnormal but the parathyroid hormone levels are normal or high. Other abnormalities are short stature, obesity, subcutaneous nodules, short fourth metacarpals and learning difficulties. There may be teeth enamel hypoplasia and calcification of the basal ganglia. A related state, in which there are the physical characteristics of pseudohypoparathyroidism but the calcium, phosphate and PTH are all normal, is called pseudopseudohypoparathyroidism. There may be a positive family history of both disorders in the same kindred.

Treatment of acute symptomatic hypocalcaemia is with an intravenous infusion of calcium gluconate. The 10% solution of calcium gluconate must be diluted as extravasation of the infusion will result in severe skin damage. Chronic hypocalcaemia is treated with oral calcium and high doses of vitamin D analogues, adjusting the dose to maintain the plasma calcium concentration just below the normal range. Hypercalcuria is to be avoided as it may cause nephrocalcinosis and so the urinary calcium excretion should be monitored.

Hyperparathyroidism results in a high calcium level, which in turn produces constipation, anorexia, lethargy and behavioural effects, polyuria and polydipsia. Bony erosions of the phalanges may be seen on a wrist radiograph. In neonates and young children, it is associated with some rare genetic abnormalities (e.g. William syndrome), but in later childhood can be secondary to adenomas occurring spontaneously or as part of the multiple endocrine neoplasia (MEN) syndromes. Severe hypercalcaemia is treated with rehydration, diuretics and bisphosphonates.

Adrenal cortical insufficiency

Congenital adrenal hyperplasia is the commonest non-iatrogenic cause of insufficient cortisol and mineralocorticoid secretion (see Ch. 11).

Primary adrenal cortical insufficiency (Addison disease) is rare in children. It may result from:

• An autoimmune process, sometimes in association with other autoimmune endocrine disorders, e.g. diabetes mellitus, hypothyroidism, hypoparathyroidism

• Haemorrhage/infarction – neonatal, meningococcal septicaemia (usually fatal)

• X-linked adrenoleucodystrophy, a rare neurodegenerative metabolic disorder

• Tuberculosis, now rare.

Adrenal insufficiency may also be secondary to hypopituitarism from hypothalamic–pituitary disease or from hypothalamic–pituitary–adrenal suppression following long-term corticosteroid therapy.

Presentation

Infants present acutely (Box 25.9) with a salt-losing crisis, hypotension and/or hypoglycaemia. Dehydration may follow a gastroenteritis-like illness, from which the child recovers until the next episode. In older children, presentation is usually with chronic ill health and pigmentation (Fig. 25.9).

Box 25.9 Features of adrenal cortical insufficiency

Acute	Chronic
Hyponatraemia	Vomiting
Hyperkalaemia	Lethargy
Hypoglycaemia Dehydration Hypotension	Brown pigmentation (gums, scars, skin creases)
Hypoglycaemia Dehydration Hypotension	Growth failure
Circulatory collapse

Figure 25.9 Buccal pigmentation in adrenal cortical insufficiency (Addison disease). This 9-year-old boy presented with salt craving and pigmentation. (Courtesy of Dr Steven Robinson.)

Diagnosis

This is made by finding hyponatraemia and hyperkalaemia, often associated with a metabolic acidosis and hypoglycaemia. The plasma cortisol is low and the plasma ACTH concentration high (except in hypopituitarism). With an ACTH (Synacthen) test, plasma cortisol concentrations remain low in both primary adrenal failure and in long-standing pituitary/hypothalamic Addison disease. A normal response excludes adrenal cortical insufficiency.

Management

An adrenal crisis requires urgent treatment with intravenous saline, glucose and hydrocortisone. Long-term treatment is with glucocorticoid and mineralocorticoid replacement. The dose of glucocorticoid needs to be increased by three times at times of illness or for an operation. Parents are taught how to inject intramuscular hydrocortisone in an emergency. All children at risk of an adrenal crisis should wear a MedicAlert bracelet.

Summary

Adrenal cortical insufficiency

• Usually due to corticosteroid therapy, congenital adrenal hyperplasia or, rarely, Addison disease

• May result in an adrenal crisis requiring urgent treatment.

Cushing syndrome

Glucocorticoid excess in children is usually a side-effect of long-term glucocorticoid treatment (intravenous, oral or, more rarely, inhaled, nasal or topical) for conditions such as the nephrotic syndrome, asthma or, in the past, for severe bronchopulmonary dysplasia (Box 25.10 and Fig. 25.10). Corticosteroids are potent growth suppressors and prolonged use in high dosage will lead to reduced adult height and osteopenia. This unwanted side-effect of systemic corticosteroids is markedly reduced by taking corticosteroid medication in the morning on alternate days.

Figure 25.10 Facial obesity from prolonged course of high-dose corticosteroids for bronchopulmonary dysplasia in a preterm infant. Such prolonged courses are no longer used. Additional oxygen therapy is being given via nasal cannulae.

Other causes of glucocorticoid excess are rare. It may be ACTH-driven, from a pituitary adenoma, usually in older children, or from ectopic ACTH-producing tumours, but these almost never occur in children. ACTH-independent disease is usually from corticosteroid therapy, but may be from adrenocortical tumours (benign or malignant), when there may also be virilisation; these usually occur in young children. A diagnosis of Cushing syndrome is often questioned in obese children. Most obese children from dietary excess are of above-average height, in contrast to children with Cushing syndrome, who are short and have growth failure.

If Cushing syndrome is a possibility, then the normal diurnal variation of cortisol (high in the morning, low at midnight) may be shown to be lost – in Cushing syndrome the midnight concentration is also high. The 24-h urine free cortisol is also high. After the administration of dexamethasone, there is failure to suppress the plasma 09.00 h cortisol levels. Adrenal tumours are identified on CT or MRI scan of the abdomen and a pituitary adenoma on MRI brain scan. Adrenal tumours are usually unilateral and are treated by adrenalectomy and radiotherapy if indicated. Pituitary adenomas are best treated by trans-sphenoidal resection, but radiotherapy can be used.

Inborn errors of metabolism

Although individually rare, inborn errors of metabolism are an important cause of paediatric morbidity and mortality. The specialised nature of the diagnostic tests and subsequent management often means that these patients are managed in specialist centres. However, as the prognosis for most patients depends upon the speed of diagnosis, all doctors need to be familiar with their variable presentation and diagnosis. It is often assumed that a precise knowledge of a large number of biochemical pathways is necessary to make a diagnosis, but in fact a more than adequate diagnostic approach can be based on the correct use of only a few screening tests.

Presentation

An inborn error of metabolism may be suspected before birth from a positive family history or previous unexplained deaths in the family.

After birth, inborn errors of metabolism usually, but not invariably, present in one of five ways:

• As a result of newborn screening, e.g. phenylketonuria (PKU), or family screening, e.g. familial hypercholesterolaemia

• After a short period of apparent normality, with a severe neonatal illness with poor feeding, vomiting, encephalopathy, acidosis, coma and death, e.g. organic acid or urea cycle disorders

• As an infant or older child with an illness similar to that described above but with hypoglycaemia as a prominent feature or as an ALTE (acute life-threatening episode) or near-miss ‘cot death’, e.g. a fat oxidation defect such as medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

• In a subacute way, after a period of normal development, with regression, organomegaly and coarse facies, e.g. mucopolysaccharide disease or other lysosomal storage disorder or with enlargement of the liver and/or spleen alone, with or without accompanying biochemical upset such as hypoglycaemia, e.g. glycogen storage disease

• As a dysmorphic syndrome.

Newborn screening

The parents of all babies born in the UK are offered a screening test to detect hypothyroidism and phenylketonuria (PKU). The tests are done on a spot of blood from a heel-prick collected onto a filter paper. Although it is technically possible to screen for a much larger group of disorders, this has been resisted in the UK. However, the screening programme has been extended to include cystic fibrosis, haemoglobinopathies and the metabolic disorder MCADD.

Amino acid disorders

Phenylketonuria

This occurs in 1 in 10 000–15 000 live births in the UK. It is either due to a deficiency of the enzyme phenylalanine hydroxylase (classical PKU) or in the synthesis or recycling of the biopterin cofactor for this enzyme. Untreated, it usually presents with developmental delay at 6–12 months of age. There may be a musty odour due to the metabolite phenylacetic acid. Many affected children are fair-haired and blue-eyed and some develop eczema and seizures. Fortunately, most affected children are detected through the national biochemical screening programme (Guthrie test).

Treatment of classical PKU is with restriction of dietary phenylalanine, while ensuring there is sufficient for optimal physical and neurological growth. The blood plasma phenylalanine is monitored regularly. The current recommendation is to maintain the diet throughout life. This is particularly important during pregnancy, when high maternal phenylalanine levels may damage the fetus.

Cofactor defects, which have a much poorer prognosis than classical PKU, are treated with a diet low in phenylalanine and neurotransmitter precursors.

Homocystinuria

This is due to cystathionine synthetase deficiency. Presentation is with developmental delay and eventually subluxation of the ocular lens (ectopia lentis). There is progressive learning difficulty, psychiatric disorders and convulsions. Skeletal manifestations resemble Marfan syndrome. The complexion is usually fair with brittle hair. Thromboembolic episodes may occur at any age. Almost half respond to large doses of the coenzyme pyridoxine. Those who do not respond are treated with a low-methionine diet supplemented with cysteine and with the addition of the re-methylating agent betaine.

Tyrosinaemia

Tyrosinaemia (type 1) is a rare autosomal recessive disorder caused by a deficiency of fumarylacetoacetase. Accumulation of toxic metabolites results in damage to the liver (leading to liver failure) and renal tubules (resulting in Fanconi syndrome). Untreated the disorder is fatal, but effective therapy is now available with a drug called NTBC, which inhibits an enzyme required in the catabolism of tyrosine, together with a diet low in tyrosine and phenylalanine.

Disorders presenting acutely in the neonatal period

This group includes:

• Disorders of the catabolic pathways of several essential amino acids (the branched-chain amino acids, leucine, isoleucine and valine, and odd-chain amino acids, e.g. threonine) to cause maple syrup urine disease and other organic acid disorders

• Defects in the urea cycle

• A disorder of carbohydrate metabolism – classical galactosaemia.

In these disorders, the affected child is normal at birth and after several days develops non-specific signs and symptoms shared with other more common neonatal disorders, such as generalised infection. The most common patterns of illness are:

• Vomiting, acidosis and circulatory disturbance, followed by depressed consciousness and convulsions – suggestive of one of the organic acidaemias

• Neurological features of lethargy, refusal to feed, hypotonia, drowsiness, unconsciousness and apnoea – suggestive of primary defects of the urea cycle. Improvement when given intravenous fluids but relapse if milk feeds are restarted is characteristic of classical galactosaemia.

Diagnosis is with a ‘metabolic screen’ in addition to the standard investigations for unwell infants. The ‘metabolic screen’ varies between laboratories and should be discussed with the specialist laboratory before collecting samples. The urgency should also be indicated. Both blood and urine samples are likely to be required. A simple bedside test for ketones can be helpful as heavy ketosis and acidosis in an encephalopathic infant is strongly suggestive of an organic acid disorder. In patients with acidosis, calculation of the anion gap (the sum of serum concentrations of sodium and potassium minus the sum of the concentrations of chloride and bicarbonate) can be helpful. Values >25 mmol/L (normal 12–16 mmol/L) are usually secondary to an organic acidaemia. It is good practice to collect all urine passed by the infant for possible future analysis (or until a diagnosis is established), as well as collecting a sample of blood before any blood transfusion in case the latter interferes with the interpretation of laboratory tests. Both short-term and long-term management depend on the underlying diagnosis. In the immediate emergency situation, removal of toxic metabolites and limitation of catabolism have the highest priority. Transfer to a neonatal intensive care unit, mechanical ventilation and haemodialysis are often required. Long-term management involves skilled dietetic support as well as the use of specific medications depending on the underlying diagnosis.

Disorders of carbohydrate metabolism

Galactosaemia

This rare, recessively inherited disorder results from deficiency of the enzyme galactose-1-phosphate uridyltransferase, which is essential for galactose metabolism. When lactose-containing milk feeds such as breast or infant formula are introduced, affected infants feed poorly, vomit and develop jaundice and hepatomegaly and hepatic failure (see Ch. 20). Chronic liver disease, cataracts and developmental delay are inevitable if the condition is untreated. Management is with a lactose- and galactose-free diet for life. Even if treated early, there are usually moderate learning difficulties (adult IQ 60–80).

Glycogen storage disorders

These mostly recessively inherited disorders have specific enzyme defects which prevent mobilisation of glucose from glycogen, resulting in an abnormal storage of glycogen in liver and/or muscle. There are nine main enzyme defects, some of which are shown in Table 25.2. The disorder may predominantly affect muscle (e.g. types II, V), leading to skeletal muscle weakness. In type II (Pompe disease) there is generalised intralysosomal storage of glycogen. The heart is severely affected, leading to death from cardiomyopathy. In other types (e.g. I, III) the liver is the main organ of storage, and hepatomegaly and hypoglycaemia are prominent (Fig. 25.11). Long-term complications of type I include hyperlipidaemia, hyperuricaemia, the development of hepatic adenomas and cardiovascular disease.

Table 25.2

Some of the glycogen storage disorders

Type	Enzyme defect	Onset	Liver	Muscle	Comments
Type I (von Gierke)	Glucose-6-phosphatase	Infant	+++	−	See Figure 25.11
					Enlarged liver and kidneys
					Growth failure. Hypoglycaemia
					Good prognosis
Type II (Pompe)	Lysosomal α-glucosidase	Infant	++	+++	Hypotonia and cardiomegaly at several months. Enzyme replacement therapy (Myozyme). Death from heart failure
Type III (Cori)	Amylo-1,6-glucosidase	Infant	++	+	Milder features of type I, but muscles may be affected Good prognosis
Type V (McArdle)	Phosphorylase	Child	−	++	Temporary weakness and cramps muscles after exercise Myoglobinuria in later life

Figure 25.11 Type I glycogen storage disease in a 12-year-old girl. There is truncal obesity with a distended abdomen from an enlarged liver; short stature and hypotrophic muscles; ‘doll’ facies; nasogastric feeding to maintain blood glucose levels overnight.

Management is to maintain blood glucose by frequent feeds or by carbohydrate infusion via a gastrostomy or nasogastric tube in infancy. In older children, glucose levels can be maintained using slow-release oligosaccharides (corn starch). In type II (Pompe disease), treatment with enzyme replacement therapy (Myozyme) is now available. In type III disorder, a high-protein diet is recommended to prevent growth retardation and myopathy.

Hyperlipidaemia

Hyperlipidaemia is one of the main risk factors for coronary heart disease. Identification and treatment of hyperlipidaemia in childhood may delay the onset of cardiovascular disease in later life.

Children should be screened for hyperlipidaemia if they are at increased risk – if a parent or grandparent has a history of coronary heart disease before 55 years of age or if there is a family history of a lipid disorder. At present, screening all children is not thought justifiable in view of the many uncertainties about selecting who should be treated, what treatment should be given and its effect on outcome.

If the serum cholesterol is high (>5.3 mmol/L) on random testing, fasting serum cholesterol, triglyceride and low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol are measured. Secondary causes of hypercholesterolaemia should be considered, such as obesity, hypothyroidism, diabetes mellitus, nephrotic syndrome and obstructive jaundice.

Familial hypercholesterolaemia (FH)

This autosomal dominant disorder of lipoprotein metabolism is due to a defect in the LDL receptor. About 1 in 500 of the population are affected. The serum LDL cholesterol concentration is markedly raised (>3.3 mmol/L). The condition is associated with premature coronary heart disease, which occurs in half by 50 years of age in males and by 60 years in females. Skin and tendon xanthomata (Fig. 25.12) may be present, but are uncommon in childhood. Drug therapy is considered in children aged 10 years and older and depends on how high the LDL cholesterol concentration is raised, if there is a family history of premature coronary heart disease (<55 years of age), if there is evidence of tissue lipid deposition (xanthomata or bruits) and other non-lipid risk factors, e.g. diabetes. The main drugs used are the non-systemically acting bile acid sequestrants and more recently the HMG-CoA reductase inhibitors, the statins. Although bile acid sequestrants are moderately effective, compliance remains a major problem with them. Statins have been shown to be effective in children, without adverse effects on growth, maturation or endocrine function. The fibrate drug fenofibrate has also been shown to reduce LDL cholesterol and to be well tolerated by children and adolescents.

Figure 25.12 Severe skin xanthomata. In this child, it was secondary to liver failure and resolved within weeks of liver transplantation.

Homozygous disease is very rare and much more severe, causing xanthomata in childhood and clinical cardiovascular disease in the second decade. Affected children require referral to a specialist centre. Response to drugs is variable, depending on the gene mutation. Liver transplantation has been tried.

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