12 Endocrinology and diabetes

This has become an important public health problem, which has achieved epidemic levels in the developed world. In the UK approximately 20% of children and adolescents are either overweight or obese. Obesity in childhood strongly predicts obesity in adulthood. Obesity is an important risk factor for the development of life-threatening disease in later life, including type 2 diabetes mellitus (T2DM), hypertension, cardiovascular disease, and cancer.

Obesity implies increased central (abdominal) fat mass, and can be quantified using a number of clinical surrogate markers. BMI is the most convenient indicator of body fat mass (see Fig. 12.1).

Other measures of obesity include:

The worldwide increase in incidence in obesity has been mainly observed in Western countries and in other developed societies. Risk factors for the development of obesity include the following:

So-called idiopathic (or ‘simple’) obesity is by far the commonest cause of obesity accounting for up to 95% of cases. It is multifactorial in origin and represents an imbalance in normal nutritional–environmental–gene interaction, whereby daily calorie (energy) intake exceeds the amount of calories (energy) expended:

Obesity may be associated with other identifiable underlying pathological conditions.

Obesity is a recognized feature characterizing the phenotype of a number of genetic syndromes.

This includes taking a detailed clinical and family history.

Laboratory investigations are directed at excluding secondary causes of obesity:

Severe obesity is associated with the following comorbid conditions, which should be screened for at the time of assessment.

In children and adolescents with obesity the prevalences of impaired glucose tolerance (IGT) and T2DM have been estimated to be in the region of 20–25% and 4%, respectively.

An oral glucose tolerance test should be considered when one or more of the following risk factors are present.

There is currently no consensus on the best approach to treating childhood obesity. Treatment requires a multidisciplinary approach.

Population-based intervention and prevention strategies may be more effective than approaches targeted at the obese individual.

This is the most common form of diabetes mellitus in children and adolescents (90% of cases). It is an autoimmune disorder characterized by T-cell mediated destruction and progressive loss of pancreatic β-cells leading to eventual insulin deficiency and hyperglycaemia.

The incidence of Type 1 diabetes mellitus (T1DM) has been increasing, but shows marked geographical variation. In Europe the highest incidence rates are seen in the Nordic countries (Finland, Sweden). During childhood there are two peaks in presentation, one between ages 5 and 7yrs and the other, larger peak, just before or at the onset of puberty. Seasonal variation in presentation of T1DM is also observed with a peak seen in the winter months.

The cause of T1DM involves both genetic and environmental factors. Over 20 different T1DM susceptibility genes have been identified. The insulin-dependent diabetes mellitus (IDDM1) gene locus, which represents the human leukocyte antigen (HLA) DR/DQ locus on the major histocompatibility complex, accounts for the greatest susceptibility.

The role of various environmental interactions and triggers is controversial.

T1DM is a chronic autoimmune condition.

The onset of symptoms evolves over a period of weeks. Symptoms are a reflection of insulin deficiency resulting in increased catabolism and hyperglycaemia. In the majority, first presentation is usually made in the early symptomatic phase with:

Other less common symptoms include:

Failure to recognize these symptoms will result in delayed or late diagnosis of T1DM and possible presentation with DKA (see  pp.98–101, 413). The risk of first presentation of T1DM with DKA is increased when non-specific symptoms of diabetes may go unrecognized:

Emphasis should be put on:

The diagnosis is readily established in a symptomatic child with a random blood glucose level >11.1mmol/L. Other investigations:

The initial care and subsequent long-term management of patients with T1DM should be delivered by a specialist paediatric diabetes team. All newly diagnosed patients must start insulin therapy as soon as possible. An intensive programme of education and support is needed for the child and parents. The aims of management of T1DM are:

An intensive programme of education and counselling is needed in the first few days/weeks to cover the fundamental principles about T1DM and its management.

A considerable amount of time and need for repetition is required to deliver this information. The process of education and support is a continual one with a need for regular review and updates of knowledge.

Diet and insulin regimen need to be matched to optimize glycaemic control. Instruction on and application of carbohydrate counting techniques are required. A healthy diet is recommended with a high complex carbohydrate and relatively low fat content.

Table 12.1 describes the various insulin analogue preparations (created by minor amino acid substitutions to the ‘native’ human insulin molecule).

The daily requirement for insulin varies with age:

Insulin is administered SC, usually as a bolus injection. A number of patients receive insulin in the form of a continuous SC insulin infusion (CSII) delivered by a pump device. Insulin injection sites include the SC tissues of the upper arm, the anterior and lateral thigh, the abdomen, and buttocks.

There is a variety of different daily insulin injection therapy regimens. The choice of regime is a compromise between achieving optimal therapy and minimizing psychosocial development. The patient and family must have input into the choice.

The simplest regimen. Two injections per day. Each injection is a mix of short/rapid-acting insulin plus an intermediate-acting insulin. Traditionally 2/3 of the total daily dose is given at breakfast and 1/3 given before/at the evening meal.

Note: Less hypoglycaemia with rapid analogue insulin use.

Improvement and intensification of the two-dose regimen:

Delayed evening intermediate-acting insulin results in reduced frequency of nocturnal hypoglycaemia.

This regimen attempts to mimic physiological secretion. Low level, background, basal insulin provides for fasting and between meal insulin requirements and larger acute doses of fast-acting insulin are given to provide for prandial requirements.

Current insulin infusion pumps are reliable and portable. CSII therapy can be used in children of all ages. Short/rapid-acting insulin is administered as a continuous insulin infusion. Meal time boluses and ‘blood glucose correction’ boluses are administered when required.

Insulin doses are adjusted based on home blood glucose monitoring. Generally it is best not to alter the basic insulin regimen every time the blood glucose levels are outside the target range (4–10mmol/L). Rather, recorded blood glucose levels should be reviewed and insulin adjustments should be made to correct recurrent profiles that are either too low or high. Insulin doses are adjusted by 5–10% at a time.

Applies the principle that the amounts of fasting/rapid acting insulin given at mealtimes are adjusted and matched according to the amount of CHO consumed.

All children with T1DM will experience an episode of hypoglycaemia. Symptoms develop when blood glucose <3.5mmol/L. The frequency of hypoglycaemia is higher with more intensive insulin regimens and in young children. Symptoms and signs include:

Occasionally, sudden onset of hypoglycaemia may result in unconsciousness and seizures. Children experiencing frequent episodes of hypoglycaemia may fail to develop the typical (i.e. counter-regulatory/adrenergic) symptoms of hypoglycaemia. Avoidance of hypoglycaemia usually results in restoration of warning symptoms.

The frequency is thought to be high in T1DM (up to 50%). Nocturnal hypoglycaemia should be suspected when fasting early morning blood sugars are repeatedly high, despite seemingly adequate overnight insulin cover (secondary to hypoglycaemia counter-regulation). Detection and confirmation of nocturnal hypoglycaemia can be achieved by utilizing a SC continuous glucose monitoring system (CGMS) device.

Acute episodes of mild to moderate symptomatic hypoglycaemia can be managed with oral glucose (glucose tablets or sugary drink). Oral glucose gels applied to the buccal mucosa can be used in the child who is unwilling or unable to cooperate to eat. Severe hypoglycaemia can be managed in the home with an intramuscular injection of glucagon (1.0mg). This is available as a specific injection kit.

During illness and other physiological stresses (e.g. following injury) insulin requirements dramatically increase in response to the body’s increased catabolic state. Blood glucose should be monitored more frequently than usual and insulin doses may need to be increased. Insulin must be continued at all times, even though oral intake of food and fluids may be decreased. Urine or plasma ketones must be monitored and, if elevated, are a sign of increased insulin needs and possible impending DKA.

If the child is unable to maintain hydration (e.g. due to excessive vomiting) or cannot take in adequate carbohydrate to avoid hypoglycaemia then the child should be evaluated by the diabetes or other medical team and consideration given to treatment with IV fluids and insulin infusions (see DKA).

See also  pp.98–101. DKA is caused by a decrease in effective circulating insulin associated with elevations in counter-regulatory hormones (glucagon, catecholamines, cortisol, GH). This leads to increased glucose production by the liver and kidney and impaired peripheral glucose utilization with resultant hyperglycaemia and hyperosmolality. Increased lipolysis, with ketone body (beta-hydroxybutyrate, acetoacetate) production causes ketonaemia and metabolic acidosis. Hyperglycaemia and acidosis result in osmotic diuresis, dehydration, and obligate loss of electrolytes. Ketoacid accumulation also induces an ileus, resulting in nausea and vomiting and an exacerbation of the dehydration.

The frequency of DKA occurring at T1DM onset, or diagnosis, is 10/100 000 children and is more common in children <4yrs of age. In established T1DM the frequency of DKA is approximately 1–10% per patient per year. The risk of DKA is increased in children with: poor metabolic control; previous episodes of DKA; peripubertal and adolescent girls; children with psychiatric disorders, including those with eating disorders; and those with difficult family circumstances.

Mortality rates for DKA are 0.15–0.31%. Cerebral oedema (CeO) accounts for 57–87% of all DKA-related deaths. The incidence of DKA-associated CeO is 0.46–0.87%. Reported mortality from CeO is high (21–25%) and significant morbidity is evident in 10–26% of all CeO survivors.

The risk of developing microvascular or macrovascular complications is related to the duration of diabetes and to the degree of glycaemic control achieved over time. Patients who achieve and maintain good glycaemic control (i.e. HbA1c 7.0% or less) have a lower risk. Genetic factors may also influence the risk of complications. The conditions outlined in Box 12.2 require screening.

Significant changes are rare before onset of puberty. Background retinopathy (microaneurysms, retinal haemorrhages, soft and hard exudates) may be seen. Pre-proliferative/profilerative retinopathy rare (  p.920).

Both the conditions should be screened for annually from age 11yrs (or from 9yrs if duration of DM >5yrs). MA screening by EMU estimation of urinary albumin: creatinine ratio. Retinopathy screening by digital retinal photography.

Patients with T1DM are at increased risk for a number of other autoimmune disorders.

The most important of these are the following:

Testing for thyroid autoantibodies, thyroid function tests (TSH and free T4), together with a coeliac disease antibody screen (transglutaminase or endomysial antibodies), should be carried out on an annual basis for the early detection and treatment of these disorders.

Glycated haemoglobin index (HbA1c) measured every 3–4mths.

T2DM is a multifactorial and heterogeneous condition in which the balance between insulin sensitivity and insulin secretion is impaired. The condition is characterized by hyperinsulinaemia; however, there is relative insulin insufficiency to overcome underlying concomitant tissue insulin resistance.

T2DM is emerging as a significant health problem with increasing incidence in most developing countries. The increasing frequency of T2DM parallels the upward trend in childhood obesity in these populations. In the USA, T2DM now accounts for up to 45% of the new cases of diabetes diagnosed in childhood.

T2DM is not an autoimmune disease. There is no association with HLA-linked genes; however, there is a strong genetic basis, which is thought to be polygenic. The known risk factors for the development of T2DM are as follows.

Clinical presentation ranges from mild incidental hyperglycaemia to the typical manifestations of insulin deficiency. Presentation with DKA may occasionally be seen. Frequent clinical findings include evidence of obesity and acanthosis nigricans.

Current diagnostic prerequisites for T2DM are:

Not infrequently the distinction between T1DM and T2DM at initial presentation may be difficult.

All patients with T2DM require the same type and degree of educational support and clinical follow-up as for patients with T1DM. Long-term management goals are the same as for T1DM (see  p.408).

Specific treatment goals should in addition include the following:

Mild (incidental) T2DM should initially be managed with lifestyle interventions aimed at lowering caloric intake (low fat; reduced CHO diet) and increasing physical activity. Where these interventions fail, pharmacological therapy is added. In children, the oral insulin sensitizing agent metformin is added as a first step; however, if glycaemic targets remain difficult to achieve insulin therapy should be included.

A clinical heterogeneous group of disorders characterized by an autosomal dominant mode of inheritance, onset usually before the age of 25yrs, and non-ketotic diabetes at presentation. The condition is due a primary defect in β-cell function and insulin secretion. Six different types have been identified due to mutations in 6 different genes (see Box 12.3).

Rare (1/400 000–500 000 live births). Defined as hyperglycaemia requiring insulin therapy occurring in the first few weeks of life, transient (50–60%) and permanent forms are recognized.

The prevalence of CFRD increases with age (˜9% between ages 5 and 9yrs; 26% between ages 10 and 19yrs). It is primarily due to a defect in pancreatic insulin secretion, although modest insulin resistance is also recognized. Insulin is recommended for all patients with CFRD.

A rare, heterogeneous group of disorders. Genetic mutations resulting in insulin receptor and post-receptor signalling defects underlie the mechanism of severe insulin resistance. Hyperinsulinaemia is present. Common clinical features include acanthosis nigricans and evidence of ovarian hyperandrogenism in females. Syndromes associated with severe insulin resistance include:

A goitre is an enlargement of the thyroid gland. It may be congenital or acquired. Thyroid function may be normal (euthyroid), underactive (hypothyroid), or overactive (hyperthyroidism). Enlargement is usually 2° to increased pituitary secretion of TSH, but may, in certain cases, be due to an infiltrative process that may be either inflammatory or neoplastic.

The commonest causes of congenital goitre are due to the transplacental transmission of factors that interfere with foetal thyroid function from the mother to the foetus:

Other rare causes include:

This is a euthyroid, non-toxic goitre of unknown cause. It is not associated with disturbance of thyroid function and is not associated with either inflammation or neoplasia. Thyroid function tests and radioisotope scans are normal. It is most common in girls during or around the peripubertal years. Treatment is not needed, although follow-up is recommended.

Solitary nodules of the thyroid are uncommon. Approximately 15% may be associated with underlying thyroid cancer. Careful evaluation is required. Potential causes of a solitary thyroid nodule include:

Investigation should include radioisotope (^99mTc) scan. Cold nodules or nodules that feel hard on palpation, or are rapidly growing should raise suspicion of thyroid cancer. Biopsy and surgical excision are indicated.

Thyroid cancer is rare in childhood. Many carcinomas of the thyroid in the past were associated with previous direct irradiation to the head and neck tissues for other conditions. Carcinomas of the thyroid are histologically classified as being either papillary, follicular, or mixed. They are usually slow growing. Girls are affected twice as often as boys. Presentation is usually with a painless thyroid nodule. Cervical lymph node involvement is often evident at time of diagnosis. Metastases to the lung may be observed radiologically, but are usually asymptomatic. Diagnosis is established by biopsy. Radioisotope scans (¹²³I or ^99mTc) demonstrate reduced uptake. Thyroid function tests are usually normal.

Thyroidectomy (subtotal or complete) is indicated. Radioiodine therapy after surgery is often given. Post-ablative oral thyroid hormone replacement therapy is needed. Prognosis is usually very good, even with presence of cervical node and/or metastases at diagnosis.

See  pp.440, 615.

Hypothyroidism may be due to a number of conditions that result in insufficient secretion of thyroid hormones. Congenital hypothyroidism is a relatively common condition, occurring in approximately 1/4000 births. It is twice as common in girls than in boys.

The causes of congenital hypothyroidism include the following:

Usually non-specific; they are difficult to detect in first month of life. They include:

In most developed countries there are national neonatal biochemical screening programmes.

Thyroid imaging is also recommended to determine whether the cause is due to thyroid dysgenesis or due to hormone biosynthetic disorder.

Without early hormone replacement therapy a number of adverse sequelae may occur.

The earlier the treatment with oral thyroid hormone replacement therapy is initiated the better the prognosis: levothyroxine (initial dose 10–15micrograms/kg/day).

Monitor serum TSH and T4 levels:

This is uncommon and is usually detected at the time of neonatal thyroid screening. It is characterized by slightly elevated serum TSH level in presence of otherwise normal serum T4 levels. It is probably due the transplacental transmission of maternal thyroid antibodies to the child in utero. Presumed cases do not need treatment, but must be monitored. TSH levels that remain persistently elevated after a few months or low T4 levels should be treated with oral levothyroxine.

A relatively common condition with an estimated prevalence of 0.1–0.2% in the population. The incidence in girls is 5–10 times greater than boys.

Acquired hypothyroidism may be due to a primary thyroid problem or indirectly to a central disorder of hypothalamic–pituitary function.

Hypothyroidism due to either pituitary or hypothalamic dysfunction.

The symptoms and signs of acquired hypothyroidism are usually insidious and can be extremely difficult to diagnose clinically. A high index of suspicion is needed.

Diagnosis is dependent on biochemical confirmation of hypothyroid state.

Thyrotoxicosis may be associated with the following symptoms:

Graves’s disease is an autoimmune disorder with genetic and environmental factors contributing to susceptibility. Several HLA-DR gene loci (DR3; DQA1*0501) have been identified as susceptibility loci and there is often a family history of autoimmune thyroid disease (girls > boys). Graves’s disease occurs due to a predominance of stimulating type autoantibodies to the TSH receptor.

In addition to those of hyperthyroidism (see  p.424), Graves’s disease is characterized by specific features:

Clinical suspicion of Graves’s disease requires confirmatory blood test:

The aims of therapy are to induce remission of Graves’s disease with antithyroid drugs (carbimazole or propylthiouracil) and, if necessary, to bring the symptoms of thyrotoxicosis (anxiety, tremor, tachycardia) under control using a β-blocking agent (propranolol). Two alternative regimens are practised.

Antithyroid therapy is usually given for 12–24mths in children, before considering a trial off treatment. Thyroid function (serum-free T4; TSH levels) should be monitored at regular intervals (1–3mths).

Following completion of treatment 40–75% of children will relapse over the next 2yrs. Relapses may be treated with a further course of antithyroid drugs, although definitive therapy with radioiodine is being offered as the first-line treatment. Thyroid surgery is another approach for management of relapses. Following ablative treatment (either radioiodine or surgery), lifelong thyroxine replacement therapy will be required.

(see  p.124)

Inflammation of the thyroid gland that may result in goitres. Initial thyrotoxicosis is usually followed by hypothyroidism. Recognized causes include:

This is the most common cause of thyroid disease in childhood and adolescence and is the most common cause of hypothyroidism in developed countries.

Clinical presentation is usually insidious with a diffusely enlarged, non-tender, firm goitre. Most children are asymptomatic and biochemically euthyroid. Some children may present with hypothyroidism. A few children may have symptoms suggestive of hyperthyroidism, i.e. ‘Hashitoxicosis’.

The clinical course is variable. Goitres may become smaller and disappear or may persist. Many children who are initially euthroid eventually develop hypothyroidism within a few months or years of presentation. Periodic follow-up is therefore necessary.

Only required for the management of either hypothyroidism (see  p.424) or hyperthyroidism if present (see  p.426).

This is uncommon. Often preceded by respiratory tract infection.

Organisms include Staphylococcus aureus, streptococci, and Escherichia coli (rarely, fungal infection). Abscess formation may occur.

The age of onset and manifestations will depend on the underlying cause. Clinical features may be subtle and a high index of suspicion is often required. Typically, clinical features are gradual in onset with partial insufficiency leading to complete adrenal insufficiency with impaired cortisol responses to stress and illness (adrenal crises):

Note: Random basal cortisol levels are often within the normal range and cannot be relied on. Inappropriately low basal cortisol during ‘stress’ suggests adrenal insufficiency. A basal cortisol level of >550nmol/L usually excludes this diagnosis. An elevated early morning (09.00 hours) ACTH level for the level of cortisol is suggestive of primary adrenal insufficiency.

Usually required to establish a diagnosis of adrenal insufficiency and are used to demonstrate inappropriately low serum cortisol responses to physiological or pharmacological stimulation of the adrenal glands.

Primary adrenal insufficiency requires both glucocorticoid and mineralocorticoid replacement therapy. 2° adrenal insufficiency requires glucocorticoid therapy only.

An adrenal (or Addisonian) crisis is an acute exacerbation of an underlying adrenal insufficiency brought on by ‘stresses’ that necessitate increased production and secretion of cortisol from the adrenal gland. This is a life-threatening emergency and should be treated if there is a strong clinical suspicion rather than waiting for confirmatory test results. Typical causes include infection, trauma, and surgery. Symptoms include:

A state of glucocorticoid (cortisol) excess. The commonest cause of hypercortisolaemia is iatrogenic, due to exogenous steroids. Hyperfunction of the adrenal cortex resulting in excess cortisol secretion may have 1° (adrenal or ACTH-independent) or 2° (ACTH-dependent) causes. The term Cushing’s disease applies to an ACTH-secreting pituitary tumour. All other causes of glucocorticoid excess are often referred to as Cushing’s syndrome.

In young children (<5yrs) adrenal disorders are the most common, non-iatrogenic, cause of hypercorticolism. In neonates and infants, McAS should be considered. In older children and adolescents Cushing’s disease is most common.

All causes of hypercortisolaemia are characterized by the following pattern of clinical signs and symptoms.

Note: Other signs may be present depending on the underlying cause. Children with adrenal tumours may have signs of abnormal virilization and masculinization (early pubic hair, hirsuitism, acne, clitoromegaly) due to excess adrenal androgen secretion.

These are directed at establishing a diagnosis of hypercortisolism and thereafter at differentiating between ACTH-dependent and ACTH-independent causes (see Box 12.4).

Congenital adrenal hyperplasia (CAH) is a family of disorders characterized by enzyme defects in the steroidogenic pathways that lead to the biosynthesis of cortisol, aldosterone, and androgens. The relative decrease in cortisol production, acting via the classic negative feedback loop, results in increased secretion of ACTH from the anterior pituitary gland and to subsequent hyperplasia of the adrenals. All forms of CAH are inherited in an autosomal recessive manner, and their clinical manifestation is determined by the effects produced by the particular hormones that are deficient and by the excess production of steroids unaffected by the enzymatic block.

The causes of CAH include deficiencies in the following steroidogenic pathway enzymes:

Deficiency of the 21-hydroxylase enzyme is the most common form of CAH, accounting for over 90% of cases.

CAH due to deficiency of the 21A-hydroxylase enzyme arises as a result of deletions or deleterious mutations in the active gene (CYP21) located on chromosome 6p. Many different mutations of the CYP21 gene have been identified, causing varying degrees of impairment of 21A-hydroxylase activity that result in a spectrum of disease expression. CAH can be classified according to symptoms and signs and to age of presentation.

The incidence of CAH due to 21A-hydroxylase deficiency has been reported to be in the region of 1 in 10,000–17,000 in Western Europe and the USA, with an overall worldwide figure of approximately 1/14,000 births.

‘Classic’ CAH is diagnosed by demonstrating characteristic biochemical abnormalities, which are present regardless of severity, age, and sex of the infant:

Note: It may be difficult to distinguish elevated androgen levels from the physiological hormonal surge that occurs in the first 2 days of life. These tests should be postponed or repeated after 48hr of age.

In the ‘salt-wasting’ form, the aldosterone deficiency results in hyponatraemia, hyperkalaemia, and metabolic acidosis. However, these are not specific findings and can cause diagnostic confusion with children presenting with more common causes of renal tubular dysfunction, such as acute pyleonephritis.

Required in all patients. In addition to treating cortisol deficiency, this therapy also suppresses the ACTH-dependent excess adrenal androgen production. Standard therapy usually consists of: hydrocortisone: oral 15mg/m²/day in 3 or 4 divided doses.

As in other disorders associated with cortisol insufficiency, during periods of stress and illness increased amounts (e.g. double or triple dose) of glucocorticoid therapy are required.

For the salt-wasting form of CAH only: fludrocortisone: oral 50–300micrograms/day.

Resistance to mineralocorticoid therapy is usually seen in infancy. Sodium chloride supplements are often required during this period of life to maintain normal electrolyte balance. Once a normal solid diet is established salt supplements may be discontinued.

Sodium chloride solution: oral, added to feed, 2–10mmol/kg/day in divided doses.

Reconstructive surgery (clitoral reduction and vaginoplasty) is usually performed in infancy in females with significant virilization of the external genitalia.

Regular monitoring of patients by a specialist team is required in order to ensure the child’s optimal growth and development.

The principal mineralocorticoid secreted by the adrenal gland is aldosterone. Increased production may result from a primary defect of the adrenal gland (primary hyperaldosteronism) or from factors that activate the renin–angiotensin system (secondary hyperaldosteronism). Hypokalaemia and hypertension are typical features.

Characterized by hypokalaemia and hypertension. There is suppression of the renin–angiotensin system with low plasma renin levels. Children may have no symptoms, the diagnosis being established after the incidental finding of hypertension. Chronic hypokalaemia may result in muscle weakness, fatigue, and poor growth.

This occurs when excess aldosterone production is secondary to elevated renin levels. Hypertension may or may not be present.

Reduced aldosterone production or activity is rare and may be due to congenital or acquired causes.

This is a family of endocrine neoplasia syndromes that are inherited in an autosomal dominant manner:

The molecular genetic defects for these syndromes have been identified and genetic screening is available. Patients with these conditions require close surveillance and screening (biochemistry, radiology, etc.).

The condition is characterized by the following clinical features.

MEN type 2 belongs to a family of three syndromes (MEN type 2A; MEN type 2B; familial medullary thyroid cancer) characterized by activating mutations in the RET proto-oncogene. Medullary thyroid cancer is a common feature in all the syndromes.

Isolated medullary thyroid cancer.

This condition is due to a mutation in the VHL gene. This is a tumour repressor gene that is located on chromosome 3.

The condition is characterized by the following features:

Characterized by the following triad of clinical features:

See also  pp.531, 662, 946. Two types of neurofibromatosis (NF) are recognized. Type 1 (NF-1; also known as von Recklinghausen’s disease) is an autosomal dominant condition due to a mutation of the NF-1 gene ( Chapter 25).

NF-1 may be associated with endocrine abnormalities:

Most causes of low calcium (hypocalcaemia) can be explained by abnormalities of vitamin D or PTH metabolism or by disordered kidney function. The principal manifestations of hypocalcaemia are related to neuromuscular irritability and include tetany and paraesthesiae.

Chronic hypocalcaemia may be asymptomatic. The child’s age is helpful in determining the differential diagnosis of hypocalcaemia.

See  p.93.

Low serum parathyroid hormone levels in childhood may be due to the following:

Characterized by end-organ resistance to the actions of PTH. It is a genetic disorder due to a defect in the G_2° A-adenylate cyclase signalling system common to the PTH receptor and other endocrine receptors belonging to the G protein-receptor family (e.g. TSH, LH, FSH). See Table 12.2.

A disorder of the growing skeleton due to inadequate mineralization of bone as it is laid down at the epiphyseal growth plates. There is a characteristic widening of the ends of long bones and characteristic radiology. Osteomalacia occurs when there is inadequate mineralization of mature bone. Both rickets and osteomalacia may be present at the same time.

Malnutrition and calcium deficiency are common causes worldwide. Vitamin D deficiency is rare in developed countries, although inadequate exposure to sunlight and exclusive breastfeeding of 6–12mths during infancy are well recognized causes.

Dietary; malabsorption.