Steroid	Relative glucocorticoid activity	Relative mineralocorticoid activity
Hydrocortisone (cortisol)	1	1
Cortisone acetate (11-deoxycortisol)	0.8	0.8
Prednisone	4	0.8
Prednisolone	4	0.8
Methylprednisolone (6 alpha-methylprednisolone)	5	0.5
Fludrocortisone (9 alpha-fluorocortisol)	10	125
Betamethasone (9 alpha-fluoro-16 beta-methylprednisolone)	25	0
Dexamethasone (9 alpha-fluoro-16 alpha-methylprednisolone)	25	0

21-OHD CAH prenatal diagnosis and intervention

This area may be mentioned in the long-case discussion. Prenatal treatment of CAH attributable to 21-OHD by administration of corticosteroids (dexamethasone) to the mother is most commonly performed in females with a previously affected child. Informed consent must be obtained from the parents before prenatal treatment is contemplated. There are possible maternal adverse effects with CAH, the genital outcome is variable and there may be long-term effects on children, which are presently unknown. Masculinisation of the external genitalia begins at 6–7 weeks’ gestation; if treatment before this suppresses the fetal pituitary–adrenal axis, it could prevent ambiguous genitalia. Of reported cases where prenatal treatment has occurred, it was successful in three quarters of them (one third normal genitalia, two thirds mildly virilised) and unsuccessful in a quarter.

Maternal complications from dexamethasone have included features of Cushing’s syndrome, marked weight gain, irritability, mood swings, hypertension and significant striae with permanent scarring. These adverse effects occurred in about one third of women treated until delivery; of these women, one third would not undergo such treatment again in a future pregnancy. The diagnostic tests (DNA for CYP21A2 from chorionic villous cells) are obtained at 8–9 weeks’ gestation. This means that treatment has to be commenced (at 5 weeks) before it is known what sex the fetus is (at 9 weeks) and whether the fetus has CAH. If the fetus is a male or an unaffected female, maternal treatment can be ceased. This means that eight mothers and babies will have to be treated to prevent the disease in one baby, as only one in eight will be an affected female.

Mothers who have previously had some medical conditions themselves—such as psychiatric diagnoses, hypertension or diabetes—should not be treated. If mothers do opt for treatment, the usual dose is 20–25 mcg/kg per day in three divided doses, started no later than the ninth week of gestation. Maternal monitoring must continue throughout pregnancy, including serum oestriol to determine adequacy of fetal adrenal suppression and fasting blood sugar monthly.

Management of acute adrenocortical insufficiency (adrenal crisis)

Candidates can explore thoroughly their understanding and practical application of the underlying pathophysiology of CAH through discussion of a hypothetical presentation of the long-case patient with 21-OHD CAH in adrenal crisis.

Adrenal crisis is most commonly seen with an intercurrent illness. Precipitating stresses include febrile illnesses, vomiting and diarrhoea, surgery or anaesthesia. Symptoms are attributable to cortisol deficiency (lethargy, disorientation), aldosterone deficiency (acute dehydration and collapse, salt craving, diarrhoea) or a deficiency of both (nausea, vomiting, weight loss, muscular weakness).

Signs include shock, dehydration, muscular weakness, hypotension and decreased pulse pressure (dehydration, decreased vasomotor tone). Examination should include a finger-prick blood glucose level. Hypoglycaemia occurs from decreased gluconeogenesis.

Investigations should include diagnostic pre-treatment blood and urine chemistry—decreased serum sodium and chloride, along with increased urinary Na loss, increased serum K, raised blood urea, low blood glucose, and acidosis on blood gas. An ECG may demonstrate low-voltage, wide PR interval, peaked T waves from hyperkalaemia due to lack of aldosterone. Plasma renin activity (PRA) is elevated in mineralocorticoid deficiency and ACTH is elevated. Electrolyte abnormalities take a few days to develop and may not be present in acute crisis.

Immediate management

1. Assess and secure the airway, breathing and circulation (the ABCs).

2. Insert an IV cannula; take blood as above.

3. Restore the circulating volume with an infusion of normal saline (isotonic, 0.9%) with added glucose to make up to 5% glucose. Start with a 20 mL/kg bolus. Correct hypoglycaemia. Aim to replace fluid and electrolytes over the next 24–48 hours.

4. Give bolus hydrocortisone IV (or IM if IV access is difficult):

Dose under 2 years—25–50 mg.

Dose 2–5 years—50–100 mg.

Dose over 5 years—100–200 mg.

Repeat hydrocortisone dose 6-hourly. Although both cortisol and aldosterone are low, only cortisol is needed during acute treatment. Avoid corticosteroids with negligible mineralocorticoid activity (e.g. dexamethasone) during resuscitation. (Remember that dexamethasone only affects dextrose, it is fairly useless in an adrenal crisis; whereas hydrocortisone is called this because it affects water balance via its effects on sodium absorption—that is, it has a mineralocorticoid effect—so it is the drug of choice in adrenal crisis.)

5. Hyperkalaemia may need further correction with insulin and glucose.

6. Treat precipitating stress: sepsis, trauma.

Diabetes mellitus

There have been a number of recent advances in the knowledge, understanding and management of type 1 diabetes (T1DM; also called insulin-dependent diabetes mellitus, IDDM). Insulin pumps have become a core therapy in Australia, being used by 16.5% of patients under 18 years at the time of writing (2010). Closed-loop systems are expected to evolve, with the addition of continuous glucose monitoring systems (CGMS) allowing fully automated blood glucose control, the ideal effectively being an artificial external pancreas, a combined insulin and glucagon pump with CGMS. In 2009, the Medtronic Paradigm Veo pump came on to the market; this pump monitors glucose 24 hours a day, alerts patients when a blood sugar level requires attention and stops insulin delivery if hypoglycaemia occurs; this furthers the technology towards ‘closing the loop’. The incidence of T1DM continues to rise worldwide at 3–5% per year, presenting at a younger age. Best practice guidelines have been produced to guide transition of young people with T1DM from paediatric to adult care. There have been further advances in understanding the interplay between genetic susceptibility and environmental factors in the pathogenesis of T1DM.

Diabetic children and adolescents represent a large and readily available group of patients who are frequently suitable as long cases. They may have problems related to inadequate control of their disease, compliance with treatment (especially adolescents), prevention of complications, difficult-to-manage behavioural problems, associated coexistent diseases such as autoimmune thyroid disease or coeliac disease, or other underlying chronic illnesses such as cystic fibrosis or β-thalassaemia major.

Background information

T1DM affects 1 in 1000 children (and 1 in 400 by adolescence). Incidence increases with age. The main genetic factor determining susceptibility to T1DM lies within the major histocompatibility complex (termed IDDM1). There is an association with certain HLA haplotypes: more than 90% of patients with T1DM have HLA-DR3 and/or HLA-DR4 (class II antigens located on the short arm of chromosome 6, at 6p21); 55% have a DR3/DR4 combination, most commonly DR4-DQ8/DR3-DQ2 (1 in 5 in families of diabetics versus 1 in 25 of the general population). DR3/DR4 heterozygosity is seen most frequently in children who develop T1DM under 5 years of age. For children who carry both of the highest-risk HLA haplotypes (DR4-DQ8/DR3-DQ2), the risk of being diagnosed with T1DM by 15 years is 1 in 20; if there is a sibling with T1DM and the same haplotypes, the risk is then 55%. One non-HLA gene is recognised as contributing to around 10% of the family aggregation of T1DM: this is termed IDDM2 and is situated on chromosome 11p5.5. This locus maps to a variable number of tandem nucleotide repeats (VNTR) of the insulin gene. Different sizes of the VNTR are associated with a risk of T1DM, the long form of VNTR being associated with protection from T1DM. A meta-analysis of data combined from most of the genomewide studies of linkage to T1DM, has been carried out by the Type 1 Diabetes Genetics Consortium; this shows that most of the genetic risk for T1DM is conferred by the class II genes encoding HLA-DR and HLA-DQ, as well as one or more additional genes within the HLA region. At least 50 inherited susceptibility loci for T1DM are known. An excellent resource noting all the genes implicated in T1DM, and constantly updated, is T1Dbase (http://www.t1dbase.org); it includes a table of all known T1DM loci, and clear diagrams of chromosomes, showing the position of each locus. Almost every chromosome has at least one locus identified. Apart from the genes in the HLA region, the majority of these loci affect T-cell function, including antigen-driven T-cell activation and cytokine signalling, proliferation or maturation.

Sibling studies previously had shown that approximately two thirds of the susceptibility to developing T1DM is linked to the HLA system. Compared to the proband, identical twins have a 40–50% chance of developing diabetes, HLA identical siblings have a 15–20% risk, HLA haploidentical siblings a 5–8% risk and non-identical siblings only a 1–2% risk. The role of viral agents in the aetiology has been discussed for years. Children with congenital rubella have a far greater incidence than the general population: this is the only environmental trigger conclusively associated with T1DM.

T1DM is associated with other autoimmune-type diseases (such as Hashimoto’s thyroiditis, Addison’s disease, primary ovarian failure and vitiligo) and with coeliac disease. However, the role of autoantibodies in the pathogenesis of T1DM has not been established. T1DM is considered a T-cell-mediated disease; islet tissue from patients with recent-onset T1DM shows insulitis, with an infiltrate made up of CD4 and CD8 T-lymphocytes and macrophages.

The development of T1DM in relatives of T1DM patients can be predicted by detecting islet-related antibodies; detection of two or more autoantibodies (GADA, IA-2 or insulin autoantibodies) has a positive predictive value of more than 90%.

Prevention of complications of T1DM

The DCCT Study (Diabetes Control and Complications Trial) involved 1441 volunteers with T1DM, ages 13–39, who had had T1DM for at least 1 but less than 15 years, and no, or minimal, diabetic eye disease; it compared intensive control of blood glucose (keeping HbA_1c [glycosylated haemoglobin] as close to 6% as possible) versus standard control of blood glucose. Patients were studied for an average of 6.5 years. The DCCT study showed that intensive blood glucose control decreases the risk of eye disease (retinopathy) by 76%, kidney disease by 50% and nerve disease (neuropathy) by 60%. The trial ended, and was reported, in 1993, but 90% of patients were followed up, and a second study, the EDIC Study (Epidemiology of Diabetes Interventions and Complications), reporting in 2005, assessed both microvacular (eye, kidney and nerve) and macrovascular disease, including incidence and predictors of various forms of cardiovascular disease (including myocardial infarction, cerebrovascular accidents, and requirement for cardiac surgery). The EDIC study showed that intensive blood glucose control decreases the risk of any cardiovascular disease event by 42%, and non-fatal myocardial infarction, cerebrovascular accident or death from any cardiovascular cause by 57%. The EDIC study showed that the benefits noted for the microvascular complications involving the eyes, kidneys and nerves during the DCCT study persisted after that study was completed. This longer-lasting benefit from tight glucose control has been termed ‘metabolic memory’.

Diagnosis

Type 1 diabetes can be diagnosed in children as follows:

• Patients with the ‘classic’ symptoms of T1DM, namely the triad of polydypsia, polyuria and weight loss despite polyphagia, are diagnosed by having a random blood sugar level (BSL; the commonly used term for plasma glucose level) above 11 mmol/L. Some units recommend a level of 14 mmol/L, but in practice the diagnosis is usually clear cut, and the level much higher than either figure.

• Asymptomatic patients require two criteria: a fasting BSL above 7.8 mmol/L, plus a 2-hour postprandial BSL above 11 mmol/L. Alternatively, a formal oral glucose tolerance test (GTT) demonstrating a sustained elevation in BSL above 11 mmol/L at 2 hours is required, as well as a similarly elevated intervening value taken between the time the glucose load (which is 1.75 g/kg, up to 75 g) is given and the 2-hour value. Again, this is fairly theoretical, as doubtful cases requiring a GTT for diagnosis are very rare.

History

Initial diagnosis

1. Initial symptoms: for example, early symptoms preceding the classic triad, lack of weight gain, nocturia, behaviour change, altered school performance, changed vision (blurring), tempo of onset (developing over days, weeks or months pre-diagnosis).

2. Immediate pre-diagnosis symptoms: polydypsia, polyuria, weight loss despite polyphagia.

3. Symptoms associated with ketoacidosis: for example, vomiting, abdominal pain, clouding of consciousness.

4. Where, when and how the diagnosis was made, length of hospital stay, education given, treatment in hospital, treatment at discharge.

Progress of the disease

1. Details of subsequent hospitalisations (frequency, indications, usual length of stay, usual outcome).

2. Complications of the disease: for example, eye problems with cataracts, retinopathy, joint problems with limited joint mobility (LJM), severe hypoglycaemic reactions.

3. Complications of treatment (e.g. fat atrophy or hypertrophy, insulin allergic reactions); degree of control (number of episodes of ketoacidosis, frequency of hypoglycaemic symptoms).

4. Monitoring of the disease: how often seen in clinic, usual investigations performed, how often seen by local doctor.

5. Changes in management: for example, increase in insulin administration from daily to twice daily, twice daily with additional short/ultra-short-acting or basal bolus regimen, use of insulin pump, altered dosages due to occult nocturnal hypoglycaemia, changeover from human insulin to analogues.

6. At what age did the patient begin to administer his or her own insulin?

Current status

1. General health: lethargic or energetic.

2. Insulin type, dose, regimen (which sort, how much, when, given by whom, where, rotation of sites; modifications with raised BSL, sporting activities, intercurrent illness or dining out), compliance with treatment.

3. Diet prescribed (whether portions/exchanges used, glycaemic index, recommended foods), diet actually taken, alcohol intake (adolescents), involvement of dietician, any restrictions (adhered to or not).

4. Hypoglycaemia: how often, what symptoms (e.g. sweating, pallor, tremulousness, hunger, headache, odd behaviour, lethargy, crying, bad temper, lack of coordination, dizziness, vomiting, convulsions, loss of consciousness, early morning headaches after nocturnal ‘hypo’, restless sleep); usual precipitants; anticipatory strategies for prevention of ‘hypos’; response to ‘hypos’ such as taking fast-acting sugars (e.g. glass of orange juice with added sugar, glass of lemonade, jelly beans) followed by a small protein and complex carbohydrate snack (e.g. bread, biscuits); ever any need for intramuscular glucagon? (Note: if no ‘hypos’ have occurred, BSL may have been too high.) Any evidence of ‘hypoglycaemia unawareness’?

5. Control: hypoglycaemia (see above); hyperglycaemia (e.g. any nocturia, polyuria, blurred vision, weight loss, excessive weight gain, disturbance of menstrual periods in postpubertal girls); BSL readings (usual levels, when performed, how often, by whom, response to high level); usual HbA_lc levels; urine testing (how often, what indications); amount of school missed in the last few months, vaginal thrush, other infections such as pilonidal sinus, infected ingrown toenail.

6. Other problems: for example, adolescent self-image, compliance issues.

Social history

1. Impact on child: self-image, reaction of school friends, coping with giving insulin, dietary restrictions, exercise, amount of school missed.

2. Impact on siblings: sibling rivalry, risk of diabetes.

3. Impact on parents: family finances, employment, concern regarding future complications, genetic counselling.

4. Social supports: Diabetes Association, access to social worker, government benefits obtained.

5. Coping: who attends the clinic with the patient, level of education of the child and parents, contingency plans for intercurrent illnesses or severe hypoglycaemia causing loss of consciousness, access to local doctor/paediatrician/hospital.

6. Peer pressures, risk-taking behaviours.

Family history

Other affected members, other autoimmune diseases (e.g. thyroid disease).

Associated diseases

Autoimmune (e.g. thyroid disease), underlying chronic illness (e.g. cystic fibrosis, congenital rubella).

Management

This involves the use of insulin, diet and regular exercise, with the following aims:

Age-specific aspects of control

The expectations at different ages vary. There are three groups:

1. Infants to preschoolers. The main goal is to avoid hypoglycaemia and preserve cognitive function (in line with the findings of the DCCT). The acceptable range for BSLs at this age is between 6 and 15 mmol/L, and the HbA_1c between 8.0 and 9.5 gm%.

2. School-age to puberty. Again, avoidance of hypoglycaemia is a top priority. Acceptable ranges: BSL 4–10 mmol/L; HbA_1c 8.0 gm%.

3. Adolescence. Acceptable ranges: BSL 4–8 mmol/L; HbA_1c as low as possible. It may be that postpubertal control is more important than prepubertal; this is unclear.

Insulin therapy

Average dosage requirements are as follows:

1. ‘Honeymoon’ period: 0.5 units per kilogram per day (or less).

2. Preadolescent: 1.0 unit per kilogram per day.

3. Adolescent: 1.0–2.0 units per kilogram per day (increase with pubertal growth spurt and reduce later when growth has finished).

The ‘honeymoon’ period, which tends to commence about 2 weeks after diagnosis, occurs in about two thirds of newly diagnosed patients (especially older boys); the nadir of insulin requirements is at an average of 13 weeks post-diagnosis.

Traditionally, insulin has been given 30 minutes before a meal. The newer ultra-short-acting insulin analogue (insulin lispro) can be given with, or just after, the commencement of a meal. It has become apparent since the development of insulin lispro that the short-acting insulins may also be effective if given with the meal.

Candidates should be familiar with the various insulin regimens. These include:

1. Daily (longer-acting only, or mixed short and longer).

2. Twice daily (see below).

3. Twice daily with additional short or ultrashort.

4. Basal bolus (three pre-meal short or ultra-short, plus longer in evening; only used in motivated adolescents).

5. Premixed (biphasic) insulin (only used for non-compliance, or inability to mix insulin).

6. Insulin pumps.

The most common regimen is a twice-daily dosage based on the ‘two thirds/one third’ rule. This is also termed a ‘split/mixed regimen’, and is based around intermediate acting insulin.

The total daily insulin dosage is divided up as follows:

• Two thirds is given in the morning (before breakfast).

• One third is given in the evening (before dinner).

And for each time it is given:

• Two thirds is given as longer-acting (intermediate) insulin.

• One third is given as short-acting insulin.

This may give insufficient control (which may well be the case in the complicated long-case patient). Most newly diagnosed diabetics are started on the twice-daily regimen, although some very young patients may require only intermediate or long-acting insulin.

The second most common regimen is the ‘basal bolus’ regimen, where the basal insulin provides background/baseline, or fasting, insulin needs, while the bolus covers eating and drinking (food and drink needs), and correction for any significant hyperglycaemia. The basal insulin is provided by long-acting insulin analogues (determir or glargine) given once or twice daily, or in the case of insulin pumps, rapid-acting insulin given at a basal rate.

Types of insulin/insulin analogue

The examiners will expect you to be familiar with the various types of human insulin, the types of insulin analogues and their durations of action. The following is a brief guide, noting the action after subcutaneous (SC) injection; refer to the latest MIMS or equivalent publication for the names of the various preparations available. There are five groups, based on onset and duration.

Rapid-acting (or ultra-short-acting) insulin analogues (insulin lispro, insulin aspart, insulin glulisine)

These are the standard insulins to be used in pumps. Ultra-short-acting analogues can be very useful in toddlers, as it can be given after food. They may improve management compliance with adolescents, and can reduce nocturnal hypoglycaemia. They can be given as an additional dose during illness or when eating extra food. Disadvantages can include the rapid fall in blood sugar, which is especially a problem in toddlers. They do not suit all patients.

1. Onset at 5–15 minutes.

2. Peak effect at 30–120 minutes.

3. Total duration of 3.5–6 hours.

Insulin analogues can replicate the prandial aspects of insulin replacement more accurately than human insulins. Appropriate use of insulin analogues allows more flexibility in timing of meals, snacks and exercise. Also, the occurrence of hypoglycaemia is less common with analogues.

Short-acting (clear) insulins (neutral/regular/soluble insulin)

These are the standard human insulins.

1. Onset at 30–60 minutes.

2. Peak effect at 2–5 hours.

3. Total duration of 6–8 hours.

Intermediate-acting insulins (isophane insulin)

Action of isophane insulins after SC injection:

1. Onset at 1–2 hours.

2. Peak effect at 4–12 hours.

3. Total duration of 16–24 hours.

Long-acting insulins (basal insulins)

These are the long-acting basal human insulin analogues: insulin glargine and insulin determir.

1. Onset at 2–4 hours.

2. For glargine, there is little peak effect: this is a ‘peakless basal insulin’; for determir, the time to maximal effect is between 3 and 14 hours.

3. Total duration of 20–24 hours. Determir has a shorter time profile than glargine, and may require twice-daily injections.

Biphasic insulins

These are premixed preparations of short-acting insulin (comprising 25–30%, depending on the preparation) and intermediate-acting insulin (making up 70–75%).

Action after SC injection:

1. Onset at 30 minutes.

2. Peak effect at 1–12 hours.

3. Total duration of 16–24 hours.

The glycaemic index (GI)

This measures how rapidly a foodstuff can raise the blood sugar. Glucose is the fastest carbohydrate available, except for maltose. Glucose is given a value of 100; other carbohydrates are rated compared to glucose. Faster-acting carbohydrates have higher numbers, and are useful to alleviate hypoglycaemia and to cover brief periods of exercise. Slower-acting carbohydrates are useful to prevent nocturnal hypoglycaemia, and for prolonged periods of exercise.

Other points about insulin

1. Insulin given intramuscularly has a higher peak and shorter duration than when given subcutaneously.

2. Insulin absorption varies with the site of the injection: it is best when injected into the abdominal wall, followed by the upper limbs and then the lower limbs.

3. Insulin should not be injected into an area that is going to be exercised, so if playing tennis, inject into the abdomen, but if doing sit-ups, inject into the thigh.

4. Lipohypertrophy can occur when the same site is used repeatedly for injection. This can be avoided by ensuring rotation of injection sites.

Specific problem areas

Intercurrent illness

Insulin must be given irrespective of illness, and adequate portions must be kept up (a portion contains 15 g carbohydrate), so that in the absence of recurrent vomiting an input of half a portion every hour is a fair guide, in conjunction with regular BSL measurements (2-hourly). If the BSL is above 15 mmol/L, then checking for ketonuria, avoidance of carbohydrates, maintenance of low-calorie fluids and a stat dose of 20% of the usual daily insulin dose are appropriate. Some units recommend giving 20% of total daily requirements as short-acting insulin regularly, every 6 hours, and stopping the longer-acting insulin temporarily (for the duration of the illness). If there is recurrent vomiting or ketonuria, the BSL should be checked hourly, and admission to hospital may be appropriate. Note that ketonuria by itself does not indicate whether the patient is responding to the management. This is because the dipstick test actually measures acetoacetate and acetone, and as acidosis improves, beta-hydroxybutyrate is converted to acetoacetate, which suggests, incorrectly, that there is a lack of response, as the ‘positive’ test persists.

Hypoglycaemic episodes

The best treatment for hypoglycaemia is prevention, which is essentially anticipation of likely provoking circumstances, such as prolonged exercise (remember that low BSL readings can occur many hours after exercise).

Symptoms of a hypoglycaemic episode (e.g. tremor, hunger, sweating, pallor, confusion, headache) without access to a glucometer, or a BSL reading below 3 mmol/L, should be treated immediately. Fast-acting sugars should be given (e.g. half a glass of lemonade, four jelly beans, or two sugar cubes: each of these approximates half a portion) if consciousness is not impaired.

All family members should be instructed in intramuscular glucagon administration, in case loss of consciousness occurs. Generally, it takes 10 minutes or so before the child starts to feel better, so a delay of this duration should not prompt further amounts of fast-acting sugar to be given, which would result in hyperglycaemia.

If a meal is due within 30 minutes of such an episode, it should be given early. If not, then additional food should be given as a complex carbohydrate (e.g. a slice of bread or a banana).

Occult nocturnal hypoglycaemia can occur in association with early morning high blood sugar readings; this is believed to be due to the effect of insulin wearing off. Isophane insulins may peak around 1 a.m, thus a very low BSL can occur at this time, but by 6 or 7 hours later the BSL may be elevated. Endocrinologists no longer believe in the ‘Somogyi phenomenon’. Nocturnal BSLs must be checked before attributing high early morning readings to insufficient evening insulin dosages. The importance of this is to recognise that the insulin dose should be decreased in the evening and not increased inappropriately by trying to ‘chase’ the hyperglycaemia.

All children with IDDM should have an identification bracelet stating that they are diabetic, their usual insulin requirements, the name of their usual doctor and the hospital they attend. If found unconscious, which will usually be due to a ‘hypo’, this will allow glucose to be administered. Hypoglycaemia-induced convulsions are common. Parents are advised to position the child appropriately, call an ambulance and administer IM glucagon. After any ‘hypo’, the patient and parents should ask why this particular episode happened.

Alternative modes of insulin delivery

Insulin pumps

An insulin pump is a small computerised device, the size of a pager, which is programmed to supply a basal infusion of insulin, subcutaneously, with increases given at meal times. Pumps have become increasingly sophisticated, and increasingly adopted as a preferred mode of therapy amongst motivated individuals, be they adolescent patients or very motivated parents. They work particularly well in the older, very motivated adolescent who is very comfortable with ‘technology’. Pumps are expensive ($5000–8000), though private health funds do cover them. Blood glucose testing is required 4–6 times per day, and then the pump has to be programmed by the user/parent, based on those measurements, while considering food intake and exercise patterns. When used optimally, compared to standard therapy, the use of pumps is associated with better blood glucose control, better HbA_1c levels and improved BMI, and reduction in the risk of long-term complications. Insulin delivery more accurately simulates the way a pancreas would deliver insulin, and pumps allow more flexibility with mealtimes, sleeping patterns, ease of adjustments when unwell and are even associated with improved school performance. Potential disadvantages include not liking the thought of being attached to a piece of machinery/technology constantly, more blood testing, superficial skin infection (or even abscesses) at the infusion site, other site problems (lipohypertrophy, skin reactions to tape, air in lines, kinks in lines) and weight gain (too easy to bolus for unhealthy snacks). A notable disadvantage of pumps is the fourfold risk of diabetic ketoacidosis (DKA); this can occur because only ultra-short-acting insulin is administered via pumps, so if the insulin runs out overnight, within a few hours the blood sugar may be rising very rapidly. For this reason, there must always be insulin and syringes available at any time, so that the patient can revert to these should the need arise. The average age of a child using a pump is around 10 years, in Australia. Children under 12 may have technical difficulties operating these pumps themselves, and may depend on their parents’ competence with the technology. Pumps can be removed for short periods (up to 2 hours) to have a shower, go swimming or play sport, but essentially they are attached 24 hours a day. A pump is only as good as its operator.

Paediatric diabetes units now have much experience in assessing whether a given patient/family is suitable for pump therapy. Most diabetic units have well-organised pathways to obtaining insulin pump management. Initially, there is a period of education, with provision of pump information, relevant web sites, usually pump information evenings, pump group education, meetings with various members of the team (the diabetic educator, dietician and the industry representative of the pump chosen) and trial periods of wearing the pump and loading it with saline. Once the decision is made to start on a pump, then usually a 2-day admission to hospital is appropriate and/or an intensive outpatient program over a few days, to receive much technical training about the pump, and cover the practicalities, such as the technique for insertion of the catheter, re-siting the catheter every 3 days and troubleshooting the more common pump problems. There is always 24-hour phone contact for a diabetic educator and there is a paediatric endocrinologist (tertiary centres) or paediatrician, on call 24 hours a day, who can be contacted through the relevant hospital. There is very frequent telephone follow-up for the first few weeks/months, and there are pump clinics in the tertiary hospitals.

The aim of pump therapy is optimal blood glucose control. In 2005, the American Diabetic Association set HbA_1c levels for four age groups: under 6 years, HbA_1c = 7.5–8.5; 6–13 years, HbA_1c < 8; over 13 years, HbA_1c < 7.5; and for adults, HbA_1c < 7. To achieve these aims, targets must be set; the day can be divided into four segments: fasting (greater than 8 hours since last meal taken); pre-meal (just prior to main meals); postprandial (less than 3 hours after a meal is eaten); bedtime (immediately prior to going to bed).

For each of these time segments, there is a target BSL range. Generally, when fasting and pre-meals and snacks, the target BSL should be 4–6 mmol/L, when postprandial and before bed, 4–8 mmol/L (6–10 mmol/L for the occasional toddler with a pump). BSL testing should be performed before meals and snacks, 2 hours after each meal or snack, at midnight, at 3 a.m., and additionally 1 and 2 hours after any correction is made, 2 hours after a re-site or set exchange, and any other time where there is any concern. The reason for the midnight and 3 a.m. tests is the decrease in BSL that often seems to occur at those times in many patients.

Basal, or background, insulin rates, are organised to reflect requirements for different time periods during the day; most patients have 4–5 different rates during the day, with modified rates for sick days, or periods of exercise/sport. The basal insulin determines the fasting and pre-meal BSLs. Bolus doses are given for meals and snacks. The insulin-to-carbohydrate ratio, which is programmed into the pump, is used to work out the bolus of insulin given with meals, and determines postprandial BSLs. Most pumps are ‘smart pumps’ and can work out the dose of insulin based on the BSL and the amount of carbohydrate to be eaten (which needs to be estimated by the patient), the numbers being entered by the patient. If the BSL is too high or low at the time, then an adjustment in bolus dose (correction bolus) can be given.

Patients should keep a written diabetes diary, and not rely on the pump, as pumps can lose data; otherwise there is little to guide the diabetic team. The patient/parent needs to take the responsibility for maintaining a ‘back-up’ written record of BSLs, food intake, the amount of insulin given and special circumstances (sport, sick days).

Changing over to a pump from syringes and needles involves, initially, changing the total daily insulin dosage by 30%, and setting the basal rate (overall) at 50% of the total daily insulin dosage. A meal bolus is worked out based on an estimated insulin/carbohydrate ratio, the ‘500 rule’, which states that: 500/total daily insulin dose = grams of carbohydrate covered by 1 unit of insulin. A correction bolus is worked out based on estimated insulin sensitivity, the ‘100 rule’, which states that: 100/total daily insulin dose = glucose drop in mml/L, for 1 unit of insulin. Patients should carry relevant guidance information for the usual variances that they are likely to encounter, such as ‘short-term adjustment guideline’ cards, which set out responses to trend arrows, low targets and high BSLs. Exceptions to the above starting parameters include initial poor control (if HbA_1c is above 9%, then do not decrease the starting dose by as much as 30%), initial high insulin requirement (if receiving 2 units of insulin per kilogram per day, then start lower, decrease by 50%) and toddlers, where the dosage of insulin may be so small that the insulin needs to be diluted first, before being loaded into the pump.

When just getting started with pump therapy, it is unwise to increase the total insulin by more than 10% in any one given 24-hour period; however, if hypoglycaemia should occur, it is acceptable to reduce the dosage by more than just 10%. Modifications in the longer term require ascertaining which of several bolus rates needs to be adjusted initially; this must be worked through systematically, testing the basal rate first, then testing the correction bolus, then testing the meal bolus—this area is too complicated to discuss briefly here. It is worthwhile candidates spending time with their hospital’s diabetic educators to work through such problems. An excellent resource has been produced by Diabetes Australia: a booklet entitled I’m Considering an Insulin Pump; Information for People with Type 1 Diabetes can be accessed at http://www.diabetesvic.org.au.

Insulin pens

Diet

Normalisation of diet is important. The usual caloric requirements are 1000 kilocalories plus 100 kilocalories per year of life: 50% of this should comprise carbohydrate, approximately 35% protein and 15% fat. Generally, the child can be given what he or she normally eats, with some degree of modification and adjustment of insulin dosage. The diet is planned using glycaemic index (GI) principles. There are few absolute restrictions. High carbohydrate, high fibre and low fat are preferable. The concept of ‘portions’ or ‘exchanges’ is less important than the use of the GI. The former terms describe set amounts of carbohydrate. One ‘portion’ contains 15 g of carbohydrate, which is equivalent to 60 kilocalories. (This is not universal; in some diabetic clinics, the size of a portion is 10 g of carbohydrate.)

The diabetic diet is planned with the help of a dietician, with the daily requirements usually divided into three main meals and three snacks. Some units use the concept of a ‘traffic light’ division of foods, namely foods that can be eaten relatively freely (‘go’, or green light, foods such as meat, fish, black coffee and clear soups), some that can be eaten in moderation (‘caution’, or amber light, foods such as bread, milk, cereals and pasta), and finally those that should be avoided in excess (‘stop’, or red light, foods such as chocolate, raw sugar, soft drinks and cakes).

Exercise

Exercise promotes glucose entry into cells and increases the number of insulin receptors. The positive effects of exercise include increased cardiovascular fitness and increased utilisation of glucose at the same insulin dosage. Exercise also allows certain normally ‘red light’ foods to be consumed, such as chocolate bars or lollies, due to the increased caloric needs.

The only difficulties are the additional considerations about diet and insulin (which are dealt with easily), and that certain groups of patients should not engage in strenuous exercise, namely those with BSL readings above 20 mmol/L, significant ketonuria, significant retinopathy and hypertension.

During acute exercise, if the BSL readings remain within the normal range or fall, this suggests fairly good control. If the BSL levels remain above normal but the patient feels unwell, this suggests poor control. It is much easier to manipulate food intake than to modify the insulin dose; it may be necessary, during strenuous exercise, to have fast-acting carbohydrates frequently.

Monitoring and control

Home BSL monitoring

The glucometer is used at least twice daily to record the BSL in a log book, which all diabetics should keep. It is useful for decisions regarding altering dosages of insulin, in particular longer-acting insulin. The goals are for a preprandial BSL of 4.0–10.0 mmol/L (in adolescents and older, between 4.0 and 8.0 mmol/L) and a postprandial value of below 10 mmol/L. Some units recommend checking BSL readings 2 hours after breakfast and dinner, and using the results to alter short-acting insulin if needed.

Certain patients can be a problem in terms of the accuracy of their BSL recordings. Beware the ‘dumb cheat’ who does the test but fakes the results (the solution here is to use a memory glucometer), and the ‘smart’ cheat, who does not do the test, and cannot do it if asked because he does not know how.

Glycosylated haemoglobin (HbA_1c)

This is a useful indicator of metabolic control over the preceding 6 weeks to 3 months. The HbA_1c levels are as follows: normal, 4–6%; excellent control, 7–8%; good control, 8–9%; unacceptable, 9–10%; bad, >10%.

Usually the child does the test at home, on special blotting paper, and posts the sample to the hospital every 3 months.

Glycosylated albumin (fructosamine)

Like HbA_lc, this gives an indication of recent diabetic control, but over the preceding 2–4 weeks.

Urine tests

Urine should be free of ketones and have glucose below 1% for 80–90% of the time. It is important to check that the test tablets or dipsticks are not out of date and spoiled. Urine should be tested for glucose and ketones when the BSL is above 15 mmol/L.

Some centres measure quantitive 24-hour urine glucose excretion every 3–4 months as an additional means of assessing control (maximum excretion less than 7% daily dietary carbohydrate is a reliable index of satisfactory control).

Routine follow-up

These children should be seen every 3–4 months. On each occasion, the child’s growth (height, weight, percentiles, maturation) and evidence of any complications should be documented (for the method of examination, see the short case in this chapter) and then managed accordingly. Proteinuria is checked for with dipstick testing, and if positive, a 24-hour urinary protein collection is performed. Fixed proteinuria suggests significant nephropathy. Microalbuminuria above 20 micrograms in 24 hours is predictive of development of chronic renal failure within 10 years. (Note: 1–2% of normal children have microalbuminuria.)

The other important clinical point is regular eye examination by an ophthalmologist, annually if postpubertal. Recommendations vary for prepubertal children. Routine investigations should include the following.

Initially

1. Screening for coeliac disease (occurs in 3–5% of T1DM): IgA tTG (tissue transglutaminase) antibodies (sensitivity 95%, specificity 90%); IgA EmA (endomysial) antibodies (sensitivity 90%, specificity approaches 100%); in children under 2, antigliadin IgG antibodies (children under 2 have a limited ability to produce IgA antibodies); if IgA deficient, IgG antigliadin antibodies; if screening is positive, small bowel biopsy.

2. Screening for thyroid disease: thyroid function tests, including TSH (15% of patients with T1DM develop Hashimoto’s thyroiditis, and a third of these develop hypothyroidism); if TSH is abnormal, antithyroid antibodies should be tested.

3. Screening for lipid disorders (ideally after overnight fasting): total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides.

4. Eye examination for cataracts.

Yearly

1. If prepubertal and diabetic for 5 years: check for retinopathy. Retinal photographs.

2. If pubertal and diabetic for 2 years: check for microalbuminuria. The initial screen is the albumin/creatinine ratio. The gold standard is timed overnight urine collection (minimum 8 hours). If microalbuminuria is present, monitor blood pressure. If diabetic for 5 years, check urea, electrolytes, creatinine.

3. If poor control (HbA_1c > 9%), check for neuropathy and examine the feet. This should include testing vibration sensation by tuning fork, testing sensation to light touch and testing ankle reflexes.

Two-yearly

1. Screening for coeliac disease.

2. Screening for thyroid disease.

3. Screening for lipid disorders (if pubertal; if prepubertal, then this testing is done every 5 years).

Complications

Complications are generally divided into microvascular, macrovascular and ‘other’. Despite the advances in insulin treatment, over 50% of patients with childhood-onset T1DM will still develop complications such as incipient nephropathy and background retinopathy within 12 years of T1DM. If the glycaemic control in the first 5 years is suboptimal, this shortens the time lapse before complications occur. All children who have had diabetes for 5 years, or are adolescents, should be screened for complications.

Microvascular complications

Risk factors for the development of microvascular complications include long duration of T1DM, poor control of BSL, family history of complications of T1DM, and associated medical problems, such as hypertension.

Retinopathy

This occurs to some degree in 90% or more of patients within 15 years of the onset of their T1DM. The most common lesions seen are ‘background’ lesions, which include microaneurysms, retinal haemorrhages (named according to appearance: dot, blot and flame), hard exudates, cottonwool spots (retinal nerve fibre infarcts) and venous calibre changes (loops, beading). Background retinopathy can be seen in up to one quarter of adolescent patients. More advanced lesions of ‘proliferative’ retinopathy occur in 40% of T1DM patients after 20 years of disease, but are uncommon in adolescence. These changes include signs of neovascularisation, fibrous proliferation and haemorrhage into the vitreous (which can cause sudden visual loss or retinal detachment secondary to fibrosis and traction) and can lead to glaucoma (obstruction to aqueous humour from vascular overgrowth).

Severe loss of vision occurs within 5 years in 50% of those with untreated proliferative retinopathy. The other form of retinopathy, maculopathy, causes central visual loss, mainly due to oedema and hard exudate formation at the macula. Retinopathy is documented with colour or red-free retinal photography and the severity assessed with fluorescein angiography. The treatment for early background retinopathy is maintenance of near normoglycaemia, there being some evidence that the institution of improved glucose control can actually reverse some of the changes. The treatment used for both proliferative retinopathy and maculopathy is laser photocoagulation: panretinal for the former and focal for the latter. Photocoagulation can reduce the rate of visual loss by half.

Screening for retinopathy should occur annually after 5 years of T1DM in a prepubertal child, after 2 years of T1DM in an adolescent, and as required if there are any symptoms. Smoking must be discouraged, because it accelerates vasculopathy.

Nephropathy

Up to 40% of IDDM patients will eventually develop end-stage renal failure. A microvasculopathy affecting the glomeruli (diffuse or nodular glomerulosclerosis) is the cause of the depressed glomerular filtration rate (GFR). The first sign of this process is microalbuminuria of over 20 micrograms per minute. Intermittent microalbuminuria or ‘borderline’ levels (7.6–20 micrograms per minute) increase the chance of nephropathy. Once proteinuria is persistent and easily detected, there has already been a reduction in the GFR, which is an ominous sign. There is a 95% occurrence of retinopathy in newly uraemic diabetics, on the basis of the same pathological process, microangiopathy, afflicting both the glomerulus and the retina. This association has been called the ‘renal–retinal syndrome’. A clinical point worth remembering is that eye status should be reviewed when any patient develops evidence of renal impairment, such as proteinuria.

Nephropathy is accelerated by hypertension, and control of the blood pressure will decrease the amount of proteinuria and slow the rate of fall in the GFR. Angiotensin-converting enzyme (ACE) inhibitors delay progression to/of nephropathy. The renal function can be monitored by plotting 1 divided by serum creatinine versus time. Once end-stage renal failure occurs, the treatment options include renal transplantation (or combined renal–pancreatic transplantation), peritoneal dialysis, haemodialysis or haemofiltration.

Screening for nephropathy should occur annually after 5 years of T1DM in a prepubertal child, and after 2 years of T1DM in an adolescent. Smoking must be discouraged.

Neuropathy

There are several forms of this:

1. Symmetric distal neuropathy, which predominantly affects sensory neurons, causing paraesthesia or pain, but can also involve the motor system.

2. Autonomic neuropathy, which can lead to postural hypotension, arrhythmias (due to denervation hypersensitivity to catecholamines), gastroparesis and impaired response to hypoglycaemia, and may be associated with painless myocardial infarction.

3. Carpal tunnel syndrome, due to the neuropathy affecting the median nerve (often the ulnar nerve is involved as well).

4. Mononeuropathy, which particularly affects cranial nerves.

All of these are infrequent in the paediatric age range. However, nerve conduction studies demonstrating subclinical peripheral nervous system involvement and evidence of sensory neuropathy are not uncommon in adolescent diabetics. The underlying pathology is thought to be a combination of polyol pathway abnormality and microangiopathy affecting the vasa vasorum, leading to axonal loss and segmental demyelination.

Macrovascular complications

Coronary atherosclerosis

Coronary artery disease is common in T1DM patients, the prevalence increasing with the duration of the disease. The extent of involvement of coronary vessels also tends to be greater (triple vessel disease more common), and it is more common in women. Clinical disease is rare in the childhood and adolescent population.

Peripheral vascular disease

Atherosclerosis is accelerated in T1DM. Peripheral vascular disease, like coronary arterial disease, is rare in the paediatric population, so that problems such as digit ischaemia are unlikely to be encountered.

Other complications

Limited joint mobility (LJM)

Thought to be due to glycosylation of periarticular tissues, limited joint mobility occurs in approximately 40% of children with T1DM. It is a painless condition that does not cause any significant disability in its early form. It affects the hands (metacarpophalangeal, proximal and distal interphalangeal joints, initially of the fifth, then the more medial fingers), wrists, elbows, spine (cervical and/or thoracolumbar) or other large joints. There seems to be a correlation between LJM and retinopathy, with an increased risk of microvascular disease developing in patients with LJM.

Requirement for psychological support

For the purposes of the long case, the usual problem is that of a non-compliant adolescent. Adolescence encompasses many developmental tasks: becoming more independent from parents; getting an education and a job; coming to terms with sexuality (sexual self-concept); and fitting in with peers and being different—‘man’, ‘dude’, ‘bro’. Teenagers can find themselves in single-parent families, or moving between parents, in low-income situations, caring for siblings or parents, or feeling cramped. On top of this, dealing with the cognitive changes includes the ability to think in an abstract manner about their future, appreciate the consequences of their behaviour (in older adolescents), and formulate hypotheses and apply logical tests. Unfortunately, it is most important to avoid serious complications in adolescence, at exactly the least receptive time of the patient’s life. For a teenager, immediate peer acceptance, which may involve nights out at parties or hotels, far outweighs the long-term benefits of near normoglycaemia. Parents’ fears at this time are of their teenagers taking risks (be they smoking, drinking, sexual risks or staying out late), and they feel out of control and worried. Parents become concerned about their teenager not managing themselves well, become frustrated, threaten about complications, and anxiety and confusion follow. Parent traps include being over-involved (parent, ‘I nag.’ versus teenager, ‘Back off, mum!’) or under-involved (parent, ‘I give up—you do it!’ versus teenager, ‘Diabetes—who cares?’), whereas the favoured approach is guiding and expressing understanding while applying limits, where, hopefully the teenager will think, ‘Diabetes is not that hard. I can do this.’

There are three important principles in parenting adolescents with a chronic illness: firstly, staying involved, which is paramount; secondly, expressing understanding while applying limits; and thirdly working as a team. Teenagers want to be understood, but want to be different from their parents. Parents have to learn to accept some things with which they do not agree; one can accept something without agreeing with it (e.g. not wanting to take insulin at school), accept that it is annoying (‘Yeah, it sucks. You must hate this—you must wish you could forget about it.’) but, without agreeing to comply with the teenager’s request, recognise that the issue must be solved (‘How about we figure out a way to sort this out?’). Parents should make it as easy as possible to live with them, recognising that they, the parents, and their teens both will get frustrated but will continually agree that the necessary management aspects for diabetes must be attended to.

Achievement of independence is the ultimate goal.

The things that doctors find difficult are the adolescent’s poor glycaemic control (typically no glucose monitoring, omitting insulin, variable diet and activity), the variable attendance at follow-up, missing appointments, risk-taking behaviour and the low priority given to health. The doctors focus on weight, what the patient is eating, routines regarding insulin administration and BSL checks. The things that adolescent patients find difficult are having a chronic illness, and the repetitive ongoing nature of diabetic management. The adolescents focus on what their peers are eating, flexibility and spontaneity in socialising, and not being different.

In chronic illness in adolescence, non-adherence is usually due to co-morbidities. Identified barriers to achieving and maintaining metabolic control include intrapersonal barriers such as: mental health issues in teens (e.g. weight and shape concerns, low mood, anxiety, substance abuse, oppositional behaviour); fear of hypoglycaemia; and learning and attention issues. There is never a problem with knowledge of diabetes per se. Interpersonal barriers include inadequate or ineffectual parental support, difficulties in the family system, single-parent families and financial stress. An effective intervention in recurrent DKA is that a responsible adult is the one who gives the insulin.

Social supports

All families of patients with T1DM should have access to an experienced social worker. The disease represents a significant financial burden for many families and the social worker can make them aware of the various government benefits to which they may be entitled. These may include child disability allowance (CDA), the isolated patients travel and accommodation scheme (IPTAS) if the patient lives more than 200 km from the hospital, and the programme of aids for disabled people (PADP: scripts for needles, syringes, glucometer, if the patient has a Health Care Card). Diabetes Australia provides access to many helpful people and ideas, including attendance at diabetic camps and the use of the National Diabetes Syringe Scheme (NDSS).

Transition from paediatric to adult care

A well-structured transition programme is important. It has been recognised that around one third of patients with T1DM have, in the past, been lost to specialist follow-up during their (planned) transfer from paediatric to adult care. To address this, in Queensland, the Mater Children’s Hospital and Queensland Health together have developed a comprehensive set of Best Practice Guidelines for health professionals, a state-wide model termed the SWEET Diabetes Transition Program. It provides clearly set out steps to guide the process, at key ages (12–13, 15, 16–17, 18+). It aims to actively involve young people in the transition process, allowing flexibility of timing, assigning a transition case worker, the choice of an adult diabetic care provider, and significant preparation and coordination. It is an excellent resource that candidates should utilise, and it can be accessed at http://www.sweet.org.au.

Pre-diabetes screening and intervention

Screening

Islet-cell antibodies may be detected in (future) patients with beta cell autoimmunity months or years before T1DM declares itself clinically. Islet-cell antibodies include antibodies against insulin (insulin autoantibodies, IAA), plus non–beta-cell-specific proteins such as glutamic acid decarboxylase (GAD) and tyrosine phosphatase (IA-2).

Prevention

Many agents have been trialled to prevent T1DM; none has succeeded as yet. There continues to be an enormous amount of research in this area, which is beyond the scope of this book. There is a wealth of information about screening and prevention of T1DM available on the internet.

Acute management of diabetic ketoacidosis (DKA)

This is an area where the candidate’s discussion of a hypothetical presentation of the long-case patient with DKA can explore thoroughly his or her understanding and practical application of the underlying pathophysiology of DKA.

The principles of treatment can be divided into five main areas, the ‘diabetic pentathlon’:

1. Water and sodium replacement.

2. Potassium replacement.

3. Correction of acid–base imbalance.

4. Insulin administration.

5. Prevention of treatment complications.

The first four areas should be well known to candidates and are not discussed here in detail. The fifth area, which can generate the most questions, is discussed briefly below.

Some complications

Cerebral oedema

Subclinical cerebral oedema occurs frequently in children with DKA. Many children fall asleep during treatment, but failure to rouse easily or onset of headache should raise suspicion of cerebral oedema (or hypoglycaemia, so checking BSL is mandatory). This typically occurs 2–24 hours after starting treatment, especially around 6–12 hours. Once clinically apparent, the mortality rate approximates 90%.

Other causes of depressed level of consciousness include: acidosis; hypoglycaemia; any rapid change in osmolality, serum sodium, serum glucose or pH; hyponatraemia; hypernatraemia; hyperosmolality; hypoxia; hypothermia; hypovolaemia; and neuroglycopenia. A cerebral CT scan should be considered if depressed level of consciousness does not respond to colloid, or if it occurs during treatment.

Risk situations include hypernatraemia (serum sodium >160 mmol/L) on presentation, hyponatraemia developing during treatment or hyponatraemia failing to correct during treatment, first presentation with DKA, poor control and children under 5 years of age. Warning features are headache, deterioration in consciousness, irritability, with later (ominous) signs of hypertension, bradycardia and dilated pupils. On occasion, there may be a presentation of polyuria, secondary to diabetes insipidus, which can be misdiagnosed as osmotic diuresis.

Prevention strategies include slow correction of fluid and glucose abnormalities, and nursing children with the head elevated. Active treatment includes 20% mannitol, 0.5 g/kg IV statim, repeated every 15 minutes, decreasing rate of fluid administration, and intubation and hyperventilation.

Hypoglycaemia (BSL <3 mmol/L)

This can present as an altered consciousness state, thus being confused with cerebral oedema. Treatment is with a bolus of 10% glucose (2 mL/kg), plus a decrease in the insulin infusion rate.

Hypokalaemia (serum potassium <3 mmol/L)

This is a potential cause of cardiac arrhythmia and death.

Short Cases

Disorders of Sexual Development (ambiguous genitalia)

This is an uncommon, but exceedingly important, case. The inability to determine the sex of a newborn immediately at birth is one of the most difficult clinical problems. Some causes are life-threatening (congenital adrenal hyperplasia, CAH). A comprehensive approach is essential and, after the diagnosis is made, issues of sex of rearing give candidates much scope for fielding interesting questions. To understand this area, some background embryology is worth reviewing, as are pathways of steroid hormone synthesis. The latter are discussed in the long case on CAH (in this chapter); the former is outlined below. This problem is also termed ‘intersex’ by some.

There are five groups of babies:

1. 46,XX DSD—genetic females with ambiguous or male phenotype.

2. 46,XY DSD—genetic males with ambiguous or female phenotype.

3. Ovotesticular DSD—usually 46,XX, genitalia usually ambiguous, gonads contain both ovarian and testicular components.

4. Sex chromosome aneuploidy DSD—for example, 45,X/46,XY mosaicism, with one streak gonad and one dysgenetic testis (also known as mixed gonadal dysgenesis).

5. Other—dysmorphic syndromes, cloacal anomalies, bladder exstrophy etc.

The most common scenario of these is female with ambiguous genitalia due to CAH.

There are two groups of babies that can be mistakenly labelled as having ‘ambiguous genitalia’. The first group are premature female infants with an unusual genital appearance; these apparent genital abnormalities are transient. The second group have perineal anatomy that is abnormal, but that is not due to any endocrine problem. They have anatomical anomalies that are not within the range of normal sexual differentiation, such as significant defects in caudal embryogenesis, which can be associated with complete aplasia of the genital tubercle such that neither a penis nor a clitoris are present. These babies do not have an intersex condition; they have anomalies of the perineum unaffected by hormones. Often, these are ano-genital malformations, not just genital ones. They are mentioned here for completeness.

There is a scoring system for the degree of masculinisation of the external genitalia described by Prader, numerically graded from 0 to 5. Prader 0 refers to normal female anatomy. Prader 5 refers to normal male anatomy. The numbers in between describe the transition from the embryological default outcome of female towards masculinity imposed by exposure to androgens. Prader 1 refers to an enlarged phallus, Prader 2 an enlarged phallus with visibly separate openings of urethra and vagina, Prader 3 refers to an enlarged phallus with a single urogenital sinus opening, and Prader 4 an enlarged phallus with hypospadias.

Until 7 weeks’ gestation, the internal genital tracts are bipotential in both XX and XY embryos. In both, the genital ducts are the wolffian (mesonephric) duct and the müllerian (paramesonephric) duct. In a normal male, the wolffian duct transforms into the epididymis, vas deferens and seminal vesicles. In a normal female, the müllerian duct transforms into the uterus, fallopian tubes and upper portion of the vagina.

If the SRY (sex-determining region on the Y chromosome) gene is present (as in a normal male), the indifferent (or ambisexual) gonad will develop into a testis. By 8 weeks’ gestation, the Sertoli cells in the testis produce müllerian-inhibiting substance/anti-müllerian hormone (MIS/AMH), while the fetal Leydig cells produce testosterone and INSL3, a peptide hormone involved in the regulation of testicular descent. The müllerian duct regresses between 8 and 12 weeks, due to MIS/AMH. Concurrently between 8 and 12 weeks’ gestation, androgens transform the genital primordium into normal male external genitalia. Testosterone is converted by 5-alpha-reductase into dihydrotestosterone. Dihydrotestosterone causes the genital tubercle to develop into the penis, with the male urethra opening at the tip, the outer labioscrotal folds to fuse into the midline scrotal raphe, forming the scrotum, and the urogenital sinus to differentiate into the bladder and the prostatic urethra. From 12 weeks until full term, enlargement of the phallus to normal penile size occurs. All external virilisation is due to androgens.

If the SRY gene is absent (as in a normal female), the bipotential gonad will develop into an ovary. Lack of testosterone and MIS/AMH leads to regression of the wolffian duct and preservation of the müllerian ducts. In the absence of androgens, the genital tubercle and the urethral plate form the clitoris and short female urethra, the labioscrotal folds remain unfused to become labia majora, and the vaginal plate, part of the posterior wall of the urogenital sinus, canalises, so forming the lower vagina.

Sexual differentiation of the brain occurs between 15 and 25 weeks’ gestation.

Examination for ambiguous genitalia

1. General examination:

• Skin: hyperpigmentation (CAH).

• Syndromal diagnosis: head, heart, hands (e.g. Beckwith; see the short-case approach to the dysmorphic child in Chapter 9).

• Hydration: assess for dehydration secondary to vomiting (CAH).

• Blood pressure: elevated in CAH due to 11 beta-hydroxylase deficiency.

2. Abdomen/pelvis/genitalia:

• Inspect for Prader grading of virilisation of external genitalia:

Prader 0: Normal female

Prader 1: Enlargement of phallus (looks more like clitoris; abnormal exposure to androgens beyond 8 weeks’ gestation)

Prader 2: Enlargement of phallus, vagina and urethra openings separate

Prader 3: Enlargement of phallus, urogenital sinus (single opening)

Prader 4: Enlarged phallus with hypospadias

Prader 5: Normal male

• Inspect the scrotum:

Fused, absent gonads (must exclude XX with CAH).

Bifid, bilateral gonads present (undervirilised XY; true hermaphrodite with bilateral ovotestes rarely).

Bifid, maldeveloped, bilateral gonads placed high (undervirilised XY, true hermaphrodite with ovotestes rarely, or XY gonadal dysgenesis [dysplastic testes]).

• Examine the midline cleft/urogenital sinus:

Gently open cleft/sinus; confirm impression of Prader stage. Skin tags with purplish tinge imply hymen present.

• Palpation for gonads:

Gonads palpable bilaterally, can be brought to base of scrotum (almost certainly testes and almost certainly male; bilateral ovotestes in true hermaphrodite rare).

Gonads palpable bilaterally but placed high (undervirilised XY, true hermaphrodite with ovotestes rarely, or XY gonadal dysgenesis [dysplastic testes]).

Gonads palpable bilaterally but asymmetrical position/descent (true hermaphrodite with a testis on one side and an ovotestis on the other, or mixed gonadal dysgenesis with a testis on one side and a streak ovary with a hernia on the other).

Single gonad palpable (almost certainly testis; other may be ovary, streak gonad [mixed gonadal dysgenesis] or ovotestis [true hermaphrodite]).

Gonads impalpable bilaterally (cannot predict gonadal status).

Rectal examination should be mentioned; the little finger can palpate the cervix and confirm a uterus.

At the completion of physical assessment, give a differential diagnosis, followed by a list of investigations appropriate for that patient. A suggested list for each follows.

Differential diagnosis

Testicular failure (undervirilised males)

1. Enzymatic—incomplete deficiency of:

• 20,22 desmolase (cholesterol → pregnenolone).

• lipoid adrenal hyperplasia due to deficiency of steroid acute regulatory protein (StAR).

• 3-beta-hydroxysteroid-dehydrogenase (pregnenolone → progesterone; 17OH pregnenolone → 17OH progesterone; DHEA → androstenedione; androstenediol → testosterone).

• 17-alpha-hydroxylase (pregnenolone → 17OH pregnenolone; progesterone → 17OH progesterone).

• 17,20 lyase (17OH pregnenolone → DHEA; 17OH progesterone → androstenedione).

• 17-beta-hydroxysteroid-dehydrogenase 17-HSD/17 ketosteroid reductase (DHEA → androstenediol; androstenedione → testosterone).

• 5-alpha-reductase (testosterone → dihydrotestosterone, DHT).

2. Anatomic:

• 46 XY pure gonadal dysgenesis (usually appear female).

• 46 XY mosaic (45 X/46 XY) or isochromosome.

3. Partial androgen insensitivity (PAIS).

Investigations

Blood tests

Chromosomes for karyotype, urea and electrolytes, 17OH progesterone, cortisol, ACTH, plasma renin activity (PRA), testosterone, DHT, DHEA, androstenedione.

Provocation tests

HCG stimulation for testosterone or DHT synthesis. Also used to assess ratio of androstenedione to testosterone (elevated in 17-HSD).

Specialised tests

Androgen binding studies; androgen receptor gene mutation analysis.

Diabetes

The introduction for this case usually requests examination for complications of diabetes or for assessment of quality of control. The candidate needs to be aware not only of the complications, but also of their time course and relation to glucose control.

It may be another chronic disease process that is causing the diabetes, such as cystic fibrosis or β-thalassaemia major. This is worth keeping in the back of your mind when initially assessing growth and Tanner staging in particular. Thus, it is relevant to scan for thalassaemic facies and hyperpigmentation, or clubbing and cough, although usually the patient will only have type 1 diabetes. Other associations may be readily apparent, such as Friedreich’s ataxia, Wolfram’s syndrome (features of which are known by the acronym DIDMOAD: Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness) or Cushing’s syndrome.

Examination

Begin by introducing yourself. Have the child adequately undressed to allow a complete examination: this usually means fully undressed down to underwear in younger children, but not necessarily in older children. Assess weight and height parameters, and percentile charts. Poor growth can be due to inadequate insulin dosage or poor compliance, associated impaired thyroid function or coexistent chronic disease. Assess pubertal status, hydration and whether the child looks sick or well. Look for any intravenous lines and read the labels on any intravenous fluid being administered.

Pick up the child’s hands. Look for any cutaneous infection or trophic changes, and carefully inspect the fingertips for prick marks indicating regular blood glucose testing. Assess for limited joint mobility (LJM) by asking the child to hold his or her hands in the ‘prayer’ position, and looking for lack of apposition of palmar aspects of the fingers (when positive, this is called the cathedral sign). If there is evidence of LJM, go on to extend the distal and proximal interphalangeal joints (normally extend to 180°), the metacarpophalangeal joints (normally extend to 60°), the wrist (normally extends to 70°) and the elbow (at least 180°). Note the colour of the palmar creases; they may be pigmented due to coexistent Addison’s disease, or underlying thalassaemia major with haemosiderosis.

Next, take, or request, the blood pressure (hypertension with nephropathy, postural hypotension with autonomic neuropathy or dehydration in ketoacidosis, hypotension with Addison’s disease).

Examine the eyes. Look carefully for squint, cataract and contact lenses (or nearby glasses). Check the visual acuity in each eye, and then the eye movements (for neuropathy). Check the pupillary reactions and the red reflex, and assess the retinae for diabetic retinopathy, of which there are three groups:

1. Background lesions include microaneurysms, retinal haemorrhages, hard exudates, cottonwool spots (small retinal infarcts) and venous beading.

2. Proliferative lesions include new vessel networks (arising from peripheral vessels or from vessels overlying the optic disc), vitreous haemorrhage and retinal detachment.

3. Maculopathy, which is rare, includes oedema and hard exudate deposition. Also look for optic atrophy (DIDMOAD).

Examine the mouth for ketotic breath and oral candidiasis, and to assess hydration. Then inspect for goitre, palpate the thyroid gland, assess movement with swallowing and auscultate if there is thyroid enlargement (associated autoimmune thyroid disease). Next, in girls, assess breast development (for delayed puberty).

The abdomen is then inspected for injection sites, fat atrophy or hypertrophy, any distension (associated coeliac disease) and pubertal status. Palpate the liver for hepatomegaly (from glycogen if ‘overinsulinised’ or fat if ‘underinsulinised’) and, in boys, note the size of the testes (for pubertal delay). Mention looking for perineal candidiasis in girls, but this does not need to be performed.

The legs are then assessed for injection sites on the thigh, and any associated fat atrophy or hypertrophy, and the lower legs for necrobiosis lipoidica diabeticorum. Look at, and between, the toes, for trophic changes or candidiasis. Finally, check for peripheral neuropathy: check the reflexes at the knee and ankle, and then examine for light touch, vibration and position sense.

Request urinalysis for glucose, ketones, protein or blood, and also the temperature chart for any infection that may have precipitated the presentation.

At this stage, the examiners may ask if there is anything further that you wish to do. Here, you can request a hearing test (DIDMOAD) and examine the ears, nose, throat and chest for any underlying infection. Finish by giving a succinct summary of the relevant findings and an overall assessment of disease control. You may then express interest in seeing the child’s medication chart for insulin dosages, and the daily recordings of blood glucose levels before the current admission.

Figure 7.1 summarises the examination for diabetes.

Figure 7.1 Diabetes

Short stature

This particular case covers more clinical ground than most and requires a very structured routine. The one outlined here proved successful both in practice cases and in the examination. It comprises four parts:

1. Observation.

2. Measurements.

3. Manoeuvres.

4. Systematic relevant examination.

Observation

Firstly, listen carefully to the patient’s age in the introduction. Then, stand back and look for any evidence of an obvious diagnosis (e.g. Turner or Noonan syndromes), any dysmorphism and any disproportion (skeletal dysplasias, rickets), and visually assess the pubertal status. The pubertal status is particularly important. Whether puberty is delayed, normal or precocious will determine the differential diagnoses to be considered as the examination progresses: for example, delayed puberty is consistent with constitutional delayed puberty, pituitary disorders and chronic diseases; normal puberty is consistent with familial short stature; and advanced pubertal staging is consistent with various causes of precocious puberty (see the short case on precocious puberty). Comment on your findings.

Measurements

Explain what you are doing as you proceed. Ask for the height and offer to measure the patient yourself: stand the child against a wall, position the head and heels appropriately, and record the height. The lower segment (LS) is the distance from the pubic symphysis to the ground. The upper segment (US) is calculated by subtracting the LS from the total height. Work out the US:LS ratio: normal values are 1.7 at birth, 1.3 at 3 years, 1.0 at 8 years and 0.9 at 18 years.

Interpretation of the US:LS ratio and arm span

• If the US:LS ratio is increased, it suggests short lower limbs (skeletal dysplasias, hypothyroidism).

• If the US:LS ratio is decreased, it suggests a short trunk (scoliosis, spondylodysplasia, osteogenesis imperfecta [OI]) or short neck (Klippel–Feil sequence).

• Next, measure the child’s arm span, and compare this to the total height. The normal arm span minus height values: −3 cm from birth to 7 years, 0 cm from 8 to 12 years, +1 cm (girls) and +4 cm (boys) at 14 years.

• A short arm span can occur with skeletal dysplasias, and an apparently long arm span with a short neck, trunk or legs.

• If the span is less than the height with a high US:LS, this may indicate short limbs and a normal trunk, or normal limbs and a long trunk.

• If the span is greater than the height with a low US:LS, this indicates a short trunk and normal limbs.

• If the span is less than the height with a low or normal US:LS ratio, this indicates short trunk and limbs.

Measure the head circumference and request the weight. Request percentile charts and progressive measurements (if not given), and calculate the height velocity (be aware of the normal range and nature of percentile charts). Request the birth parameters (for intrauterine and chromosomal causes, such as being small for gestational age [SGA]) and the parents’ heights and onsets of puberty (for family history of constitutional delayed puberty).

By now, you may well have a good indication of the type of short stature with which you are dealing.

After all these parameters have been evaluated, either (a) proceed with the manoeuvres below, particularly if the child is very short, or has obvious skeletal anomalies or a clearly disproportionate short stature, or (b) commence a systematic head-to-toe examination, and slot in the manoeuvres along the way, should they appear relevant. The order adopted is unimportant; it is the demonstration of a comprehensive approach that is required.

The mid-parental height (MPH) may be calculated: for girls, MPH = mother’s height plus (father’s height minus 13 cm)/2, ± 6 cm; for boys, MPH = father’s height plus (mother’s height plus 13 cm)/2, ± 7.5 cm.

Manoeuvres

Inspect from front

A set of manoeuvres can be performed that very rapidly screens for a number of syndromes that may be relevant in assessing short children. With each manoeuvre, stand opposite the child and demonstrate, so that he or she will mirror your movements.

Screen for asymmetry: have the child put the palms together with the arms out straight, and stand with legs together. Asymmetry occurs in Russell–Silver syndrome. Focus on the upper limbs first, then evaluate the lower limbs.

Screen for carrying angle: have the child hold the arms by their side, with palms forward. This angle can be increased in Turner or Noonan syndromes. Also, restriction of elbow extension may be detected (e.g. hypochondroplasia).

Screen for short limbs: have the child touch the tips of the thumbs to the tips of the shoulders. If the thumbs overshoot, there is proximal segment (rhizomelic) limb shortening. If the thumbs do not reach the shoulders, there might be either middle segment (mesomelic) or distal segment (acromelic) limb shortening, or alternatively the limbs may be bent (camptomelic). Thus this manoeuvre should detect proximal-segment shortening (e.g. achondroplasia), middle-segment shortening (e.g. Langer mesomelic dysplasia) or distal-segment shortening (e.g. acromesomelic dysplasia).

Screen the hands: have the child hold the palms up. Look for simian crease (Down syndrome) and clinodactyly (Russell–Silver syndrome). Note the structure of the fingers (e.g. short with hypochondroplasia), their number and any syndactyly (e.g. Apert syndrome). Turn the hands over (palms down), note the structure of the hand (e.g. trident deformity in achondroplasia) and check the nails (e.g. hyperconvex in Turner).

Ask the child to make a fist and look for a shortened fourth metacarpal (pseudohypoparathyroidism).

Inspect from the side

The child should be standing with the arms by his or her side. Note whether there is a prominent forehead (e.g. achondroplasia), flat occiput (Down), proptosis (e.g. syndromes with craniosynostosis), micrognathia (e.g. Pierre Robin sequence) or prognathism (e.g. achondroplasia). Note how far the upper limbs reach; if the limbs are short, the fingers may only reach the proximal thigh; if the trunk is short, the fingers may reach the knees. Note the shape of the back, for lordosis (e.g. achondroplasia), thoracolumbar kyphosis (e.g. achondroplasia) or crouched posture (e.g. diastrophic dysplasia).

Inspect from the back

Examine for scoliosis (and any kyphosis, which should have been noted already). Have the child bend forwards and touch the toes to determine whether any scoliosis is structural. Scoliosis can occur in dozens of syndromes, including many skeletal dysplasias, several trisomies and a number of popular examination syndromes (e.g. Noonan). Do explain what you are doing as you proceed, so that the examiners will be aware of the significance of the manoeuvres.

Examination

The formal physical examination flows well if commenced at the hands, working up to the head, and then downwards: essentially a ‘head-to-toe’ pattern. Table 7.5 (‘Additional information’) at the end of the section on short stature outlines the findings sought at each point.

Table 7.6 Manoeuvres to assess for tall stature

Hands and feet together

To detect:

• Hemihypertrophy (Beckwith, McCune–Albright, Proteus)

• Unilateral growth arrest (homocystinuria with cerebrovascular accident)

• Genu valgum (homocystinuria)

• Genu recurvatum (Marfan)

• Pes planus (Marfan)

Bend over and touch toes To detect:

• Scoliosis (Marfan, homocystinuria, Proteus, Sotos, NF-1)

• Kyphosis (with scoliosis, as above, pituitary gigantism)

Palms to floor/thumb to forearm/hyperextension fifth finger/hyperextended knees (Beighton score for hypermobility) To detect:

• Hypermobility (Marfan)

• Limitation of extension (homocystinuria)

Arachnodactyly tests: Steinberg (thumb past ulnar border)/Walker–Murdoch (wrist) To detect Marfan syndrome Tremor To detect hyperthyroidism

At the completion of the comprehensive physical examination, request results of urinalysis (e.g. type 1 diabetes mellitus [T1DM], chronic kidney disease [CKD]) and stool analysis (malabsorption from cystic fibrosis [CF], coeliac disease, inflammatory bowel disease [IBD]). Finally, summarise your findings succinctly and give a brief differential diagnosis, placing the most likely diagnosis first (see Figure 7.2).

Figure 7.2 Short stature: examination and observation

Investigations

At this stage, you may be asked what investigations you would perform. Depending on the findings, of course, the answers vary. Generally, a bone age is most useful and, in girls, a chromosomal analysis is always warranted to exclude Turner syndrome. Other investigations often ordered include thyroid function tests (hypothyroidism), electrolytes, urea and creatinine (CKD), tissue transglutaminase antibodies (coeliac disease) and growth hormone (GH) provocation testing (clonidine, arginine or glucagon), the latter only being performed after other preliminary testing is done (see Table 7.4), and poor height velocity is demonstrated. Low IGF-1 and IGFBP-3 levels are useful in predicting GH deficiency, or GH resistance, although normal levels do not exclude GH deficiency (see Table 7.4).

Table 7.5 Additional information: a more comprehensive listing of possible physical findings in children with short stature

General inspection

Diagnostic facies

• Dysmorphic syndromes (Russell–Silver, Turner, Noonan, FAS)

• Endocrine disorders (GH deficiency, Cushing, hypothyroidism)

• Other (e.g. thalassaemia)

Disproportionate stature

• Skeletal dysplasias (achondroplasia)

• Metabolic bone disease (rickets)

• Connective tissue disorders (osteogenesis imperfecta [OI])

Tanner staging

• Advanced (precocious puberty)

• Delayed (constitutional delayed puberty [CDP]; chronic illness [CKD, CHD]; endocrine disorders [hypopituitarism, hypothyroidism])

Nutritional status

• Obese (endocrine causes, syndromal causes)

• Poor (malabsorption, undernutrition, chronic diseases)

Skeletal anomalies

• Asymmetry (Russell–Silver)

• Pectus excavatum (Noonan)

• Scoliosis (Noonan, Klippel–Feil)

Colour

• Pallor (thalassaemia, nutritional deficiency, CKD)

• Sallow (CKD)

• Jaundice (CLD)

• Cyanosis (CHD, CF)

• Pigmented (thalassaemia)

Tachypnoea

• Cardiac (CCF with large VSD)

• Respiratory (CF)

Irritability (coeliac disease) Skin

• Various rashes related to nutritional deficiencies

• Erythema nodosum (IBD)

• Café-au-lait spots (NF-1, Fanconi anaemia, Russell–Silver)

Upper limbs Structure

• Clinodactyly fifth finger (Russell–Silver, Shwachman, Seckel)

• Short fourth metacarpal (pseudohypoparathyroidism, Turner, FAS)

• Trident hand (achondroplasia)

• Polydactyly (Bardet–Biedl)

Fingertips: BSL testing (T1DM) Nails

• Clubbing (CHD, CF, CLD)

• Brown lines (CKD)

• Leuconychia (CLD)

• Short (cartilage hair hypoplasia)

• Hyperconvex (Turner)

• Hypoplastic (FAS)

Fingers: swollen joints (JIA) Palms

• Simian creases (Down)

• Crease pallor (anaemia from nutritional deficiency, CKD)

• Pigmented creases (thalassaemia, long-standing CAH)

Wrists

Pulse

• Bradycardia (untreated hypothyroidism)

• Radiofemoral delay (coarctation of aorta with Turner, NF-1)

Forearms: muscle bulk (malnutrition) Blood pressure: elevated (CRF, Cushing, CAH, NF-1, Turner with coarctation) Head Size

• Small (TORCH, syndromes)

• Large (intracranial tumour, toxoplasmosis)

Shape

• Triangular (Russell–Silver)

• Frontal bossing (rickets, thalassaemia)

Consistency: craniotabes (rickets) Fontanelle

• Large (Russell–Silver, rickets, hypothyroidism)

• Bulging (intracranial tumour with raised ICP)

Hair

• Dry (hypothyroidism)

• Greasy (precocious puberty)

Eyes Inspection

• Photophobia (cystinosis)

• Hypertelorism (Noonan, William)

• Epicanthal folds (Noonan, William, Turner, Down)

• Ptosis (Noonan, pseudohypoparathyroidism)

• Squint (William, Prader–Willi, septo-optic dysplasia [SOD])

• Nystagmus (SOD)

Conjunctivae: pallor (CKD, malnutrition, thalassaemia) Sclerae

• Icterus (CLD)

• Blue (OI)

Cornea: cloudy (rubella) Visual fields: field defect (intracranial tumour, e.g. craniopharyngioma) Eye movements

• Upward gaze palsy (pineal tumour)

• Lateral rectus palsy (intracranial tumour with raised ICP)

Cataracts (rubella, Cushing, treated thalassaemia, T1DM) Fundi Papilloedema (intracranial tumour with raised ICP)

• Optic nerve hypoplasia (SOD)

• Chorioretinitis (TORCH)

• Diabetic retinopathy (T1DM)

• Pigmentary retinopathy (abetalipoproteinaemia)

Nose Midface hypoplasia (FAS) Midline dimple (hypopituitarism) Nasal polyps (CF) Anosmia (Kallmann) Mouth and chin Central cyanosis (CHD, CF) Midline defects associated with hypopituitarism

• Cleft lip (repaired)

• Cleft palate (repaired)

• Single central incisor

Delayed dentition (hypothyroidism) Glossitis (nutritional deficiency) Facial hair or acne (precocity, Cushing) Micrognathia (Russell–Silver, Turner, Seckel) Ears Low set (Turner, Seckel, Noonan) Posteriorly rotated (Russell–Silver) Hairline Low (Turner, Noonan) Neck Pterygium colli (Turner, Noonan) Short (Klippel–Feil) Scoliosis (Klippel–Feil) Goitre (hypothyroidism) Chest Inspection

• Tanner staging in girls (for precocity or delay)

• Wide-spaced nipples (Turner)

• Hyperinflation (CF)

• Sternal deformity (Noonan)

• Rib rosary (rickets)

Palpation

• Praecordium (CHD)

• Ribs for rosary (rickets)

Percuss chest: hyperresonance (CF) Auscultation

• Lung fields (CF, CCF)

• Praecordium (CHD)

Abdomen Inspection

• Distension

• Weak muscles (coeliac, nutritional deficiency)

• Ascites (CKD, CLD, nutritional deficiency)

• Hepatosplenomegaly (thalassaemia)

Tanner-staging pubic hair (for precocity or delay) Operative scars (Kasai, liver transplant, renal transplant) Access devices (e.g. Tenckhoff catheter for CKD, access ports in CF) Striae (Cushing) Injection sites (insulin in T1DM, desferrioxamine in thalassaemia) Palpation

• Abdominal tenderness (Crohn)

• Hepatomegaly (e.g. nutritional deficiency, T1DM, CF, Shwachman)

• Splenomegaly (e.g. thalassaemia, storage diseases, CF, CLD)

• Hepatosplenomegaly (e.g. thalassaemia, storage diseases)

• Enlarged kidneys (e.g. polycystic kidneys or hydronephrosis with CKD)

• Transplanted kidney (CKD)

Percussion: ascites (CKD, CLD) Auscultation: renal artery stenosis (NF-1) Posterior aspect

• Buttock wasting (malnutrition)

• Perianal fistulae (Crohn)

Genitalia Tanner-stage genitalia

• Measure penis length

• Measure testes parameters; estimate testes volume

• Advanced stage (causes of long-standing precocity, e.g. CAH)

• Delayed stage (e.g. CKD, thalassaemia, hypopituitarism)

Penile anomalies

• Micropenis (hypopituitarism)

• Hypospadias (Noonan)

Testicular anomalies: cryptorchidism (Noonan) Gait, back and lower limbs Inspection of lower limbs

• Lower limb bowing (rickets)

• Proximal, middle or distal shortening (bony dysplasias)

• Joint swelling (JIA)

• Injection marks on thighs (T1DM)

• Erythema nodosum (IBD)

• Necrobiosis lipoidica (T1DM)

• Pyoderma gangrenosum (IBD)

• Oedema of dorsa of feet (Turner)

• Clubbing of toes (CF, CHD)

Palpation: ankle oedema (CCF with CHD, CLD) Gait—standard examination screening for:

• Long-tract signs (IC tumour)

• Peripheral neuropathy (nutritional deficiency, CKD)

• Proximal weakness (Cushing)

Back

• Scoliosis

• Kyphosis

• Focal spinal shortening (irradiation for malignancy)

• Midline scar (spina bifida)

• Spinal tenderness (Cushing, rickets)

Lower limbs neurologically

• Long tract signs (IC tumour)

• Neuropathy (CKD, nutritional deficiency)

• Delayed ankle jerk relaxation (hypothyroidism)

Other Urinalysis

• pH (RTA)

• Specific gravity (CKD)

• Blood (CKD)

• Protein (CKD)

• Glucose (T1DM, Cushing)

Stool analysis

• Blood (IBD)

• Pus (IBD)

• Fat globules (CF)

• Fat crystals (coeliac)

• Glucose (T1DM, Cushing)

Stool analysis

• Blood (IBD)

• Pus (IBD)

• Fat globules (CF)

• Fat crystals (coeliac)

BSL = blood sugar level; CAH = congenital adrenal hyperplasia; CCF = congestive cardiac failure; CF = cystic fibrosis; CHD = congenital heart disease; CKD = chronic kidney disease; CLD = chronic liver disease; FAS = fetal alcohol syndrome; IBD = inflammatory bowel disease; ICP = intracranial pressure; JIA = juvenile idiopathic arthritis; LS = lower segment; NF = neurofibromatosis; OI = osteogenesis imperfecta; RTA = renal tubular acidosis; SCA = sickle cell anaemia; T1DM = type 1 diabetes mellitus; TORCH = intrauterine infections with toxoplasmosis, other (e.g. HIV, syphilis), rubella, cytomegalovirus, herpes (both simplex and varicella); US = upper segment; VSD = ventricular septal defect.

Table 7.4 Some useful investigations in the child with short stature

Investigation	Indications/relevance
Blood
Full blood examination and film	Chronic disease, anaemia
Erythrocyte sedimentation rate	Inflammatory bowel disease
Electrolytes, urea, creatinine	Chronic kidney disease
Fasting blood glucose	Diabetes
Calcium, phosphate, SAP	Rickets, hypophosphatasia
Liver function tests	CLD, nutritional deficiency
Tissue transglutaminase antibodies	Coeliac disease
Pancreatic isoamylase	Shwachman syndrome
Thyroid function tests, TSH	Hypothyroidism
Karyotype	Syndromes, e.g. Turner, Down
Somatomedin C (also called insulin-like growth factor, IGF1)	GH deficiency, coeliac, Crohn, malnutrition, hypothyroidism, T1DM (poorly controlled)
Insulin-like growth factor binding protein 3 (IGFBP-3)	GH deficiency
GH stimulation tests (arginine, clonidine, glucagon, GHRH)	GH deficiency
LH, FSH, prolactin, oestradiol, testosterone	Hypogonadism
Dexamethasone suppression test (combined high and low dose)	Cushing’s syndrome
Sweat
Sweat conductivity	Cystic fibrosis
Imaging
Bone age	Maturational delay, precocious puberty, hypothyroidism, hypopituitarism
Skeletal survey	Skeletal dysplasias
Skull X-ray	Craniopharyngioma
MRI of brain	Intracranial tumour

CLD = chronic liver disease; FSH = follicle-stimulating hormone; GH = growth hormone; GHRH = growth hormone releasing hormone; LH = luteinising hormone; SAP = serum alkaline phosphatase; TSH = thyroid-stimulating hormone.

Table 7.4 lists some relatively simple investigations that are often useful in the child with short stature. More common diagnoses appearing in the examination setting include constitutional delay in growth and puberty [maturational delay] and Russell–Silver syndrome.

Aetiologies

The mnemonic IS NICE lists various headings/causes for aetiologies of short stature:

I. Idiopathic (constitutional delay in growth and puberty [maturational delay]; familial short stature)/Intrauterine (SGA, TORCH, fetal alcohol syndrome [FAS])

S. Skeletal causes (dysplasias, OI)/Spinal defects (scoliosis, kyphosis)/Syndromes (Russell–Silver, Kallman)/Septo-optic dysplasia (SOD)

Nutritional (e.g. malabsorption)/Nurturing (deprivation)

I. Iatrogenic (steroids, radiation)

C. Chronic diseases (CKD, congenital heart disease, CF, IBD)/Chromosomal (Turner, Down)/Craniopharyngioma (or other central tumour)

E. Endocrine (e.g. GH deficiency, GH insensitivity, hypopituitarism, hypothyroidism, Cushing, T1DM, pseudohypoparathyroidism)

Two other lists worth remembering enumerate the conditions that cause short stature and obesity. They are not comprehensive, but they are simple to recall. There are five endocrine causes and five syndromal causes, as follows:

Alternative introduction to short stature—endocrine

Occasionally, the lead-in for short stature has been: ‘This child is short. Would you please examine the endocrine system’. For those who have learned a comprehensive approach such as that previously outlined, this can cause some concern. This should not be the case, as all that is required is some abbreviation of the previous system, with elimination of the irrelevant parts. Remember that assessment for Turner syndrome is part of an endocrine assessment, as is evaluation for Kallmann syndrome, septo-optic dysplasia, craniopharyngioma or other central tumour (i.e. do not forget to test the visual acuity and visual fields, examine the optic fundi and perform a gait examination) and rickets.

Tall stature

This is not a common case, but it can appear in the examination setting. The routine outlined is quite comprehensive. Like the short stature case, it comprises four parts:

1. Observation.

2. Measurements.

3. Manoeuvres.

4. Systematic relevant examination.

Observation

Start by noting the child’s age in the introduction. This is important for appropriate assessment of the Tanner staging and intellect, which are essential in this case. Introduce yourself to the child and parent. Ask the child which grade he or she is in at school, and note whether the response seems age-appropriate (impairment of intellect can occur with Beckwith–Wiedemann (B–W) or Sotos syndrome, or with homocystinuria).

Now stand back and inspect for any evidence of a Marfanoid body habitus (e.g. Marfan syndrome; multiple endocrine neoplasia type 2b [MEN 2b]; homocystinuria) or a eunuchoid habitus (e.g. Klinefelter or Kallmann syndromes), and visually assess the Tanner staging. Note whether the child is wearing glasses (e.g. myopia in Marfan syndrome or homocystinuria). Note any skeletal anomalies such as asymmetry (e.g. in neurofibromatosis type 1 [NF type 1], B–W, Proteus or McCune–Albright syndrome), pectus carinatum or excavatum (e.g. in Marfan syndrome or homocystinuria) or scoliosis (e.g. Marfan syndrome, homocystinuria, NF type 1, Proteus syndrome, Sotos syndrome), and observe any unusual posturing (e.g. hemiplegia in homocystinuria, complicated by a cerebrovascular accident due to thrombotic tendency). Comment on your findings.

Look at the skin for areas of hyperpigmentation, such as café-au-lait spots (in NF type 1, Proteus syndrome, McCune–Albright syndrome [McC–A]) or larger areas (e.g. in the sacral area in McC–A syndrome, and the epidermal naevi in Proteus syndrome), as well as subcutaneous tumours (numerous types can occur in Proteus syndrome, such as lipomata, haemangiomata and lymphangiomata). Also note whether the child has acne (various causes of precocity).

Measurements

Next, measure the patient yourself. Stand the patient against a wall, position the head and heels appropriately and record the height. Measure the lower segment (LS)—that is, the distance from the pubic symphysis to the ground—then calculate the upper segment (US), which is the height minus the LS. Work out the US:LS ratio. Normal values at various ages are listed in Table 7.2.

Table 7.2 Normal upper segment to lower segment ratios

Age	Ratio
Birth	1.7
3 years	1.3
8 years or more	1.0

If the US:LS ratio is decreased, it suggests that the lower limbs are disproportionately long (e.g. Marfanoid body habitus, eunuchoid body habitus). If the US:LS is normal, this is more in keeping with diagnoses such as familial tall stature or pituitary gigantism.

Next, measure the arm span and compare this to the total height. The normal arm span minus height values at various ages are given in Table 7.3. A long arm span occurs in Marfanoid or eunuchoid patients, or patients with other diagnoses complicated by a shortened trunk, caused by scoliosis (e.g. Sotos) or kyphosis (e.g. pituitary gigantism). If the arm span to height ratio is > 1.05, then this indicates long limbs (e.g. Marfan syndrome or eunuchoid body habitus).

Table 7.3 Normal arm span minus height values

Age	Value
Birth to 7 years	−3 cm
8–12 years	0
14 years	+1 cm in girls

Next, measure the head circumference and request the weight.

Request percentile charts, progressive measurements (if not given) and calculate the height velocity (be aware of the normal range and nature of percentile charts for this measurement). Request the birth parameters (B–W and Sotos can have large birth weights) and the parents’ heights, percentiles and onsets of puberty (ask about age of menarche for women and age when men started shaving).

Manoeuvres

Next, a series of manoeuvres can be performed to screen for a number of possible causes of tall stature. With each manoeuvre, stand opposite the child and demonstrate, so that he or she will mirror your movements. First, ask the child to put the palms together with the arms straight, and stand with the legs together. This is to screen for asymmetry (as can occur in B–W syndrome, McC–A syndrome and in NF type 1) and also allows inspection for genu valgum (homocystinuria), genu recurvatum (Marfan syndrome) and pes planus (Marfan syndrome). Next, ask the child to bend forward and touch the toes; this is to check for scoliosis (can occur in Marfan syndrome, homocystinuria, MEN 2b or Sotos syndrome) or kyphosis (can occur in conjunction with scoliosis in the above diseases, as well as in pituitary gigantism/acromegaly); if the child can do this with ease, then ask him or her to put their palms flat on the floor, while reaching down/bending forward, without any bending of the knees. This is one of the tests for hypermobility (Marfan) comprising the ‘Beighton score’—the other tests include: (i) apposing thumb to forearm with wrist flexed; (ii) passive hyperextension of the fifth finger over 90° (Gorling’s sign); and (iii) hyperextension of knees greater than or equal to 10° (genu recurvatum). In Marfan syndrome, the fifth component of the Beighton score (more than 10° hyperextension of the elbows) is not useful, as Marfan syndrome is paradoxically associated with decreased elbow extension (to < 170°). If these tests show less mobility than normal, then homocystinuria is more likely. Next, test for arachnodactyly (Marfan), using two digit-related eponymous signs: (a) the thumb (Steinberg) sign—this is an extension of the whole distal phalanx of the thumb beyond the ulnar border of the hand when apposed across the palm; and (b) the wrist (Walker–Murdoch) sign—this is overlapping of the distal phalanx of the thumb with the distal phalanx of the little finger when encircling the opposite wrist. If both these tests are normal, then Marfan syndrome is a less likely diagnosis.

Finally, ask the child to hold the arms out straight in front with the fingers spread apart and check for tremor associated with hyperthyroidism.

For a list of manoeuvres, see Table 7.6.

Table 7.7 Additional information: details of possible findings in the child with tall stature

Introduction

Impression of mental state: intellectual impairment (homocystinuria, Sotos, Beckwith–Wiedemann [B–W], Klinefelter)

General inspection

Body habitus

• Marfanoid (dolichostenomelia: Marfan, homocystinuria, MEN 2b)

• Eunuchoid (Kallman, Klinefelter)

Tanner staging

• Delayed (Kallmann, Klinefelter)

• Advanced (precocious puberty, virilisation, e.g. adrenal tumour, CAH)

Skeletal anomalies

• Asymmetry (Beckwith, NF-1, McCune–Albright [McC–A], Proteus)

• Pectus excavatum (Marfan, homocystinuria, MEN 2b)

• Scoliosis (Marfan, Sotos, homocystinuria, MEN 2b, NF-1)

Posture

• Hemiplegic (homocystinuria)

Skin

• Café-au-lait spots (NF-1, McC–A, Proteus)

• Subcutaneous tumours, e.g. Iipomata, haemangiomata (Proteus)

• Hyperpigmented areas (McC–A, Proteus)

• Acne (virilisation syndromes)

Upper limbs Arachnodactyly (Marfan, MEN 2b) Large hands (Sotos, Proteus, pituitary gigantism) Nails: thyroid acropathy (hyperthyroidism) Palms

• Warm, sweaty (hyperthyroidism)

• Pigmented creases (CAH)

Pulse: collapsing (aortic incompetence in Marfan, hyperthyroidism) Blood pressure

• Elevated (NF-1, CAH, pituitary gigantism, MEN type 2b with phaeochromocytoma)

• Pulse pressure elevated (aortic incompetence with Marfan, hyperthyroidism)

Axillae: assess pubertal staging for precocity or delay, apocrine secretion, hair, odour Head Size

• Large (Sotos, NF-1)

• Small (B–W)

Shape

• Frontal bossing (Sotos)

• Prominent occiput (B–W)

Hair

• Receding frontal hairline (Sotos)

• Dry, light, sparse (homocystinuria)

• Greasy (CAH)

Face

• Asymmetry (B–W, Proteus, NF-1, McC–A)

• Fair complexion (homocystinuria)

• Malar flush (homocystinuria)

• Café-au-lait spots (NF-1, McC–A)

• Naevus flammeus (B–W)

Eyes Inspect:

• Wearing glasses (myopia with Marfan, homocystinuria)

• Blue irides (homocystinuria)

• Prominent (B–W, hyperthyroidism)

• Exophthalmos (hyperthyroidism)

• Hypertelorism (Sotos)

• Downslanting (Sotos)

• Conjunctival neuromata (MEN 2b)

• Bluish sclerae (Marfan)

• Lens displacement (up in Marfan, down in homocystinuria)

Visual acuity

• Myopia (Marfan, homocystinuria)

Visual fields

• Bitemporal hemianopia (pituitary tumour)

• Homonymous hemianopia (cerebral thrombosis with homocystinuria)

External ocular movements

• Ophthalmoplegia (hyperthyroidism)

• Sixth cranial nerve palsy (intracranial tumour)

Cataracts (homocystinuria) Fundoscopy

• Retinal detachment (Marfan, homocystinuria)

Glaucoma (Marfan, homocystinuria) Nose Anosmia (Kallmann) Mouth and chin Lips: prominent (neuromata in MEN 2b) Tongue

• Big (B–W, pituitary gigantism)

• Nodular (MEN 2b)

Teeth

• Crowding (homocystinuria)

• Separation (pituitary gigantism)

Palate

• High, narrow (Marfan, Sotos, homocystinuria)

• Cleft (Marfan)

Chin

• Acne (sexual precocity)

• Hair (pubertal staging)

• Prognathism (Sotos, B–W, McC–A)

Ears Linear fissures in lobules (B–W) Punched-out depressions in posterior pinnae (B–W) Large (Proteus, Marfan) Neck Examine for goitre (hyperthyroidism) Chest Tanner-stage breasts in girls, hair in boys Deformity: pectus carinatum or excavatum (Marfan, homocystinuria) Praecordium: full assessment for Marfan cardiac complications, e.g. aortic regurgitation, mitral valve prolapse Abdomen and genitalia Inspect:

• Café-au-lait spots (NF-1, McC–A, Proteus)

• Herniae (Marfan, homocystinuria, B–W)

• Umbilical scar (repair of exomphalos with B–W)

• Tanner staging of pubic hair

Palpate

• Hepatomegaly (homocystinuria, B–W)

• Enlarged kidneys (Wilms’ tumour in B–W)

• Adrenal mass (tumour; isolated or associated with B–W)

• Tanner staging of genitalia

Lower limbs Asymmetry (hemihypertrophy with B–W, NF-1, Proteus; growth arrest with CVA in homocystinuria) Large feet (Sotos, Proteus, pituitary gigantism) Gait

• Shuffling gait; like Chaplin’s Little Tramp (homocystinuria)

• Hemiplegic gait (homocystinuria with CVA)

CAH = congenital adrenal hyperplasia; CVA = cerebrovascular accident: MEN = multiple endocrine neoplasia; NF-1 = neurofibromatosis type 1.

Remember, as you proceed, to explain to the examiners what you are doing and why, so that the significance of each manoeuvre will be appreciated. The formal physical examination proceeds from the hands, working up to the head and then downwards; that is, head to toe, as outlined in Figure 7.3. A comprehensive listing of possible findings is given in Table 7.7 at the end of this section.

Figure 7.3 Short stature: measurements and manoeuvres

Table 7.8 Additional information: details of possible findings on obesity examination

Introduction

Impression of mental state

• Intellectual impairment (PW, B–B, Down, Fröhlich; hypothyroidism, PHPT, some storage disorders)

• Sleepy (Pickwickian)

General inspection

Growth parameters

Height

• Short (endocrine or syndromal causes)

• Tall (simple obesity, Klinefelter)

Head circumference: enlarged (intracranial tumour, hydrocephalus with spina bifida)

Percentile charts

Calculate height velocity

Request

• Birth parameters

• Parents’ percentiles

Distribution of obesity: central (Cushing)

Skin

• Bruising (Cushing)

• Poor wound healing (Cushing)

• Café-au-lait spots (McCune–Albright syndrome)

Truncal striae

Tanner staging

• Pseudoprecocity (Cushing)

• Hypogonadism (syndromes: PW, B–B, Kallmann, Fröhlich)

• Gynaecomastia (Klinefelter)

Respiratory rate

• Hypoventilation (Pickwickian syndrome)

Head

Shape: prominent forehead and bitemporal narrowing (PW)

Size: large (brain tumour, hydrocephalus with spina bifida)

Hair

• Dry, pluckable (hypothyroidism)

• OiIy (Cushing)

Face

• Cherubic (round, immature face of GH deficiency)

• Moonface (Cushing)

• Plethora (Cushing, or secondary polycythaemia if Pickwickian)

• Telangiectasia (Cushing)

• Coarse features (hypothyroidism)

• Down syndrome facies

Eyes

• Eyebrows: loss of outer third (hypothyroidism)

• Almond-shaped eyes (PW)

• Squint (PW)

• Epicanthic folds (Down syndrome)

• Down-slanting (Down syndrome)

• Visual acuity: impaired (B–B, Fröhlich, Alström)

• Visual fields: bitemporal hemianopia (pituitary tumour)

• Cataract (posterior subcapsular in Cushing)

• Retinae

Retinitis pigmentosa (B–B, Alström)

Papilloedema (pituitary tumour, benign intracranial hypertension in Cushing)

Hypertensive retinopathy (Cushing)

Nose

• Anosmia (Kallmann)

• Midline dimple (hypopituitarism)

Mouth and chin

• Triangular upper lip (PW)

• Central cyanosis (Pickwickian)

• Midline defects associated with hypopituitarism or Kallmann

Cleft lip (repaired)

Cleft palate (repaired)

Single central incisor

• Delayed dentition (hypothyroidism)

• Oral candidiasis (Cushing)

• Tonsillar size (upper airway obstruction associated with hypoxia and hypercapnia in Pickwickian)

• Micrognathia (PW)

• Facial hair or acne (Cushing)

Neck

Goitre (hypothyroidism)

Obliteration of supraclavicular hollow, i.e. supraclavicular fat pads (Cushing)

Elevated JVP (RVF in Pickwickian)

Abdomen

Striae (Cushing)

Hepatomegaly (RVF with Pickwickian syndrome)

Adrenal mass (Cushing syndrome due to adrenal tumour)

Genitalia

• Advanced development of hair or phallus (Cushing, hypothyroidism)

• Delayed development (hypothyroidism; can advance or delay)

• Hypogonadism (PW, B–B, Fröhlich, Kallmann, Klinefelter)

Lower limbs

Inspection

• Small feet (PW)

• Skin: striae, bruises, poor wound healing (can all occur in Cushing syndrome)

• Limb shortening (with SCFE or avascular necrosis of femoral head)

• External rotation at hip (SCFE)

• Genu valgus or varus (complications)

Measure: limb lengths (for shortening, as above)

Palpate: ankle oedema (RVF in Pickwickian)

Manoeuvres

Stand child with legs together and re-inspect for:

• Leg shortening (if not measured)

• External rotation

• Genu valgus or varus

Hold arms up against resistance (proximal myopathy in Cushing)

Squat (proximal myopathy); can ‘race’ child with repeated squats; normal child should win

Walk, looking for limp with:

• Avascular necrosis femoral head (Cushing)

• SCFE (complication of obesity)

Trendelenberg’s test: positive with avascular necrosis of femoral head or SCFE

Lay patient down again for completion of lower limb examination

Lower limbs completion

Hip examination: limitation of internal rotation or abduction (SCFE)

Ankle jerks: delayed relaxation (hypothyroidism)

B–B = Bardet–Biedl syndrome; GH = growth hormone; JVP = jugular venous pressure; PHPT = pseudohypoparathyroidism; PW = Prader–Willi syndrome; RVF = right ventricular failure; SCFE = slipped capital femoral epiphysis.

If the patient appears to be quite clearly Marfanoid, the examination outlined can be substantially abbreviated and can concentrate on the skeleton, eyes and heart. At the completion of your physical examination, summarise your findings succinctly and give a brief differential diagnosis.