Mrcpch Guide Endo

MRCPCH GUIDE Endo Addison's disease is an autoimmune condition and is often part of an autoimmune polyendocrinopathy. Type I is Addison's with chronic mucocutaneous candidiasis or hypoparathyroidism or alopecia or vitiligo or Chronic active hepatitis or IDDM or hypothyroidism. Type II is with IDDM or thyroid disease. Hypercalcaemia is caused by hyperparathyroidism. Patients have low phosphate, raised calcium and raised PTH concentrations. Vitamin D toxicity can cause hypercalcaemia. Hypercalcaemia may also be seen after prolonged immobilisation, in association with malignancy and in hypophosphatasia. Hypophosphatasia is an inborn error of metabolism leading to a deficiency of alkaline phosphatase (ALP).

Type 1 DM is associated with HLA DR3 and DR4. The majority of patients have demonstrable islet cell antibodies at diagnosis Genetics play a part in the development of DM, but other factors are also important. The incidence of DM in the normal population is 0.4%, with the risk to siblings being 6%. HLA identical siblings have a risk of 12%. Twin studies suggest that one third of the susceptibility is genetic. Twin studies have suggested that the future risk of diabetes in the unaffected child is 30–50%. The presence of glutamic acid decarboxylase (GAD), islet-cell or IA-2 antibodies in the unaffected child increases the likelihood that the child will go on to develop type-1 diabetes. Children of type-1 diabetic patients have a slightly increased risk of developing the disease (3– 6% risk where the father is diabetic, 2–3% where the mother is diabetic). Twin studies in type-2 diabetes have suggested that if one identical twin develops the disease, then the risk in the unaffected twin rises to 50% or greater. Maturity-onset diabetes of the young (MODY) is a rare variant of type-2 diabetes with a very strong familial pattern of inheritance.

In Cushing’s syndrome caused by ectopic ACTH secretion, which of the following may occur? Incorrect Suppression with high dose dexamethasone

True

False

True

False

True

False

Correct Hypokalaemia

Correct Hypocalcaemia

Incorrect

Metabolic alkalosis

True

False

True

False

Correct Raised aldosterone

There is no suppression of secretion with high dose DXM. Hypokalemic metabolic alkalosis may occur

11 -Hydroxylase deficiencies can lead to hypertension. A diagnosis of adrenal failure is demonstrated by a failure of the plasma cortisol concentration to increase in response to ACTH. Demonstration of a high plasma ACTH concentration indicates primary rather than secondary (to pituitary insufficiency) adrenal failure. Random measurements of cortisol are only of value in sick patients, in whom cortisol concentrations should normally be high. Measurement of the diurnal variation in secretion (which is lost), the cortisol response to dexamethasone (decreased) or urinary cortisol excretion (increased) are used in the diagnosis of Cushing’s syndrome but have no place in the diagnosis of adrenal failure.

Hypokalaemic periodic paralysis is related to a muscle calcium-channel mutation (CAClN1A3). It is an autosomal-dominant condition; attacks usually begin in the teenage years and may remit after around 35 years of age. Potassium is normally below 3 mmol/l during an attack and symptoms resolve with the administration of potassium chloride. Attacks appear to be precipitated either by a high carbohydrate meal or by a period of rest after extreme exercise. Loss of function of muscles concerning speech, bulbar or generalised weakness may occur and attacks can last for several hours.

Breast-bud enlargement is the first sign of puberty in girls. This begins between the ages of 9 and 12 years and continues to 12–18 years. Pubic hair growth occurs next, at ages 9–14 years, and is complete at 12–16 years. Menarche occurs relatively late (age 11–15 years). Peak height velocity is reached earlier (10–13 years) and growth is completed much earlier than in boys. Antibodies to thyroid peroxidase and thyroglobulin are found in the serum of the majority of patients with Graves’ disease, in which radioisotope uptake is typically increased. A low uptake occurs in subacute (de Quervain’s) thyroiditis (in which the erythrocyte sedimentation rate (ESR) is typically elevated). Elevated T3 with a normal T4(‘T3 toxicosis’) can occur early in the course of thyrotoxicosis from any cause. The high concentrations of thyroid hormones suppress TSH secretion to very low levels in thyrotoxicosis due to thyroid disease: detectable (not always elevated) TSH in thyrotoxicosis suggests that this is caused by a pituitary adenoma secreting TSH.

Approximately 80% of patients with phaeochromocytoma complain of headaches, which are often paroxysmal. Tremor is much less common. Pallor, not flushing, is seen in those with a phaeochromocytoma and patients may complain of constipation. Flushing and diarrhoea are features of the carcinoid syndrome. Approximately one-quarter of patients experience muscle weakness, which can also be present in primary aldosteronism, another endocrine cause of hypertension.

The commonest cause of ambiguous genitalia is congenital adrenal hyperplasia. It is important that this diagnosis is made as early as possible because of the risk to the child if the enzyme deficiency is complete. Other causes of masculinisation of a female fetus are less common. They include maternal ingestion of androgenic drugs in early pregnancy, maternal Cushing's syndrome or maternal arrhenoblastoma. Less commonly, ambiguous genitalia may result from inadequate masculinisation of a male fetus or true hermaphroditism. The diagnosis can only be made after examination under anaesthetic, laparotomy and gonadal biopsy. Prior to this, congenital adrenal hyperplasia should be excluded and the karyotype known. It is extremely important that the parents appreciate that their child does have a definite sexual identity and is not going to remain somewhere between the two sexes.

Primary hypothyroidism Teratoma Tuberous sclerosis Hepatoblastoma Gigantism

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Hypogonadism is a common feature in gigantism, leading to delayed epiphyseal closure and thus a more prolonged growth period. Klinefelter's syndrome is the most common cause of primary testicular failure and results in impairment of both spermatogenesis and testosterone production. The other conditions listed are causes of precocious puberty, which is defined as the development of the menarche before the age of 8 years in girls, or of secondary sexual characteristics before the age of 9 in boys. It is accompanied by accelerated skeletal maturation and linear growth, with premature closure fo the long bone epiphyses, resulting in short stature as an adult. Precocious puberty is classified into two types: 1) True precocious puberty, caused by premature secretion of gonadotrophins, which stimulate the production of testicular androgens and sperm. This results in virilisation and an increase in testicular size. Causes include:    

idiopathic precocious puberty central nervous system lesions which affect the posterior hypothalamus, eg. craniopharyngioma, haematoma, hydrocephalus, neurofibroma, tuberous sclerosis, postencephalitic lesions hCG-secreting tumours, eg. hepatoblastoma primary hypothryoidism, probably due to direct stimulation of FSH receptors by the high circulating levels of serum TSH; testicular enlargement and other features regress with thyroxine therapy.

2) Precocious pseudopuberty results from secretion of androgens from the adrenal gland or testes. Excessive androgens result in virilisation, but sperm production is not stimulated and the testes remain small. Causes include:  

adrenocortical hyperfunction (congenital adrenal hyperplasia, virilising adrenocortical tumours) Leydig cell tumour

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McCune-Albright syndrome (hyperpigmentation, polyostotic fibrous dysplasia, multinodular goitre and other glandular hyperfunction). The commonest cause of Addison’s Disease in the UK is autoimmune adrenal disease. There are associations with other autoimmune conditions including hypothyroidism, hypoparathyroidism and vitiligo. Presenting features are usually hypoglycaemia, fatigue and muscle weakness, gastrointestinal disturbance and hyperpigmentation. Glycogen stores are low and severe hypoglycaemia may occur during fasting or intercurrent stress or illness. Hyponatraemia results from aldosterone deficiency and reduced plasma volume induced vasopressin secretion causing water retention. Acute 'Addisonian' crisis may occur as the presenting feature in a previously unsuspected case precipitated by intercurrent illness or stress. There is hypotension, dehydration, prostration and collapse.

Steroids, dopamine, and octreotide suppress TSH production. Asherman’s syndrome is amenorrhoea due to uterine synechiae after infection

Gordon’s syndrome is associated with the renal retention of sodium, causing hypertension, volume expansion, low renin/aldosterone, hyperkalaemia and metabolic acidosis. In type-4 renal tubular acidosis, metabolic acidosis occurs coupled with a low plasma bicarbonate level and hyperchloraemia.

The incidence in the UK is 13.5 in 100, 000, in China 0.6 in 100, 000, and is at its highest in Finland at 42.9 in 100, 000. There is a family history of type 1 diabetes mellitus in 10% of cases. If a sibling has type 1, the risk to the index case is 8%; if the father has type 1 the risk is 5–6%; and if the mother has type 1 the risk is 2–3%. If both parents have type 1 the risk increases to 30%. At least one type of autoimmune antibody is found in the vast majority of patients at diagnosis. Islet cell antibodies (ICA) are found in 65–80% of newly diagnosed type 1 diabetics, glutamic acid decarboxylase (GAD) antibodies are found in 65–80%.

There are three intracellular messenger pathways in which hormones may act, namely cyclic adenosine monophosphate (cAMP), intracellular calcium, or tyrosine kinase. Hormone receptors linked to cAMP do not generate cAMP directly but act via a G protein receptor on the cell surface. The G protein may be inhibitory (for example, somatostatin) or stimulatory (all other hormones). McCune–Albright syndrome and pseudohypoparathyroidism are disorders of hormone–receptor interactions. Vitamin D-dependent rickets and nephrogenic diabetes insipidus are syndromes of receptor resistance. De Morsier syndrome (also known as septo-optic dysplasia) is a developmental anomaly of the midline structures of the brain.

The gonadotrophins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are glycoproteins released form the anterior pituitary gland. They are composed of an a- and a ßsubunit. In the male, Leydig cells respond to LH, which stimulates the first step in testosterone production. In the female, LH binds to ovarian cells and stimulates steroidogenesis. FSH binds to Sertoli cells in the male and increases the mass of the seminiferous tubules and supports the development of sperm. In the female, FSH binds to the glomerulosa cells and stimulates the conversion of testosterone to oestrogen. Gonadotrophin-

releasing hormone (GnRH) stimulates the synthesis and secretion of LH and FSH. Expression and secretion of FSH are also inhibited by inhibin, which has no effect on LH. In the neonate there are high levels of gonadotrophins but these decline progressively until nocturnal increases occur leading up to the onset of puberty. In boys FSH stimulates Sertoli cells to promote spermatogenesis, and LH (luteinising hormone) stimulates Leydig cells to produce testosterone. In girls FSH stimulates the granulosa and theca cells to produce oestradiol, and LH stimulates the stromal cells to produce androgens.

Neonatal hyperthyroidism is rare. It is caused by the transplacental transfer of maternal TSH receptor antibodies. Only a minority of babies (1.5%) born to mothers with Graves disease will be affected. Symptoms commonly occur at 24–48 hours of age but may be delayed for up to 10 days if maternal antithyroid drugs cross the placenta. Those severely affected have up to 25% mortality from cardiac arrhythmias and cardiac failure. Children with Graves disease with few exceptions have some enlargement of the thyroid gland. Hyperthyroidism may cause polyuria and nocturia due to increased glomerular filtration rate. The onset in childhood is usually insidious and has often been present for some time prior to diagnosis. Many of these children experience behavioural problems and school difficulties. Approximately 50% of children treated medically will be in long-term remission by 4 years, with a continued remission rate of 25% every 2 years after this up until 6 years of treatment. Persistently high thyroid antibody titres indicate a high chance of recurrence once the treatment is stopped. Favourable factors for long-term remission using medical treatment alone include the requirement for a low dose of antithyroid medication, a small goitre, lack of eye signs, and a lower initial free thyroxine (T4). Antithyroid medication should be tapered and gradually withdrawn. Those requiring definitive treatment can be treated with radioactive iodine or thyroid surgery. The former is becoming more commonly used in paediatrics particularly in the USA and its safety profile to date has been very good. The genes for PTH and calcitonin are both located on the short arm of chromosome 11. The primary function of PTH is to prevent hypocalcaemia. The immediate effect of an increase in PTH is increased calcium absorption and increased phosphate excretion in the kidney alongside osteoclastic bone resorption. The gastrointestinal effect is delayed by 1-2 days and occurs via increased synthesis of 1,25(OH)2 vitamin D. Vitamin D-dependent rickets is a rare cause of rickets. Type 1 is secondary to deficiency of 1 hydroxylation of 25 hydroxy vitamin D; type 2 is due to resistance of 1,25(OH) 2 vitamin D. Both are treated with calcitriol, large doses are necessary in type 2. Vitamin D-deficient rickets is treated with vitamin D; hypophosphataemic rickets is treated with frequent doses of phosphate and also calcitriol as there is associated deficiency of 1-hydroxylation of 25-hydroxyvitamin D. Bone disease of prematurity is thought to be predominantly caused by phosphate and/or calcium deficiency, and is treated with phosphate and calcium supplements. Peak bone mass is attained in the third decade of life. Positive influencing factors include exercise, obesity, calcium, calcitonin, oestrogen, growth hormone (GH) and Afro-Caribbean race. Negative influencing factors include inactivity, malabsorption, anorexia, tumour necrosis factor (TNF), interleukin 1, glucocorticoids, vitamin D, PTH and Chinese and Caucasian race.

Primary amenorrhoea (a girl who has never menstruated) can be subdivided into those girls who have no evidence of sexual development and those with normal sexual development. Absence of menstruation in the absence of normal secondary sex development should be investigated by the age of 14. The likely causes include 45X (Turner's syndrome), hypothalamic or pituitary causes (craniopharyngiomas, Kallmann's syndrome, Laurence-Moon-Biedl syndrome) or chronic disease. Primary amenorrhoea with normal sexual development should be investigated by the age of 16. It is usually due to anatomical abnormalities but rarely may be due to complete androgen insensitivity syndrome or even pregnancy. Severe GH insufficiency may be congenital, acquired, isolated or associated with other pituitary hormone deficiencies. Many children with idiopathic isolated GH deficiency have a hypothalamic disorder of GHRH release, responding to a GHRH bolus by secreting GH normally. In others, high resolution CT or MR scanning demonstrates abnormalities ranging from absent septum pellucidum associated with other midline defects (septo-optic dysplasia) to pituitary hypoplasia. Acquired GH deficiency may result from intracranial tumor (e.g. craniopharyngioma) or from cranial irradiation for medulloblastoma or acute lymphoblastic leukemia. Temporary GH deficiency is seen in children with psychosocial deprivation and occurs physiologically in late prepuberty and early male puberty. GH biosynthesis and release is also impaired in other conditions (e.g. primary hypothyroidism or coeliac disease). The first physical sign of puberty in girls is usually a firm, tender lump under the center of the areola(e) of one or both breasts , occurring on average at about 10.5 years. This is referred to as thelarche. By the widely used Tanner staging of puberty, this is stage 2 of breast development (stage 1 is a flat, prepubertal breast). The first menstrual bleeding is referred to as menarche . The average age of menarche is about 12.7 years, usually about 2 years after thelarche. The pubertal growth spurt in girls begins at the same time the earliest breast changes begin. The rate of growth tends to reach a peak velocity midway between thelarche and menarche and is already declining by the time menarche occurs. In boys, testicular enlargement is the first physical manifestation of puberty (and is termed gonadarche ). Testes in prepubertal boys change little in size from about 1 year of age to the onset of puberty, averaging about 2-3 cc in volume and about 1.5-2 cm in length. Testicular size continues to increase throughout puberty, reaching maximal adult size about 6 years later. A boy's penis grows little from the fourth year of life until puberty. The prepubertal genitalia are described as Tanner stage 1. Within months after growth of the testes begins, rising levels of testosterone promote growth of the penis and scrotum . This earliest discernible beginning of pubertal growth of the genitalia is referred to as stage 2. Estradiol is produced from testosterone in male puberty as well as female, and male breasts often respond to the rising estradiol levels. This is termed gynaecomastia . In most boys, the breast development is minimal, similar to what would be termed a "breast bud" in a girl, but in many boys, breast growth is substantial. Anorexia nervosa has a female to male preponderance of 9:1. It is estimated that around 0.5– 1% of American women between 15 and 30 years of age have anorexia, and the numbers are likely to be similar in the UK. The aetiology of anorexia is unknown, but it is likely to be an interaction between environmental and genetic factors, American studies report rates of sexual abuse as high as 50% in anorexic females. Typical laboratory tests include decreased FSH, LH, oestrogens and 17-OH steroids. Free T4 and TSH levels are usually normal. Anaemia with decreased white and platelet cell count may also occur. There may be metabolic alkalosis, hypocalcaemia, hypokalaemia and hypomagnesaemia. Treatment may involve complex psychotherapy for a number of years, and referral to a specialist in the field is recommended. Patients with anorexia nervosa actively maintain an unduly low body weight. For diagnostic purposes, an ‘unduly low body weight’ may be defined as a weight at least 15% below that

expected for the person’s age, height and sex, or as a body mass index below 17.5. Amenorrhoea (in postmenarchal women who are not taking an oral contraceptive) is almost always present in these patients. The typical patient with anorexia nervosa is a female aged < 25 years with weight loss, amenorrhea and behavioural changes. There is a long-term risk of severe osteoporosis. Endocrine abnormalities include GnRH deficiency, low LH and FSH, low oestrogen in females, raised circulating cortisol, low to normal thyroxine, reduced T3, normal TSH and increased resting GH levels. Insulin is synthesised and stored by the B cells of the pancreatic islets. The B cells make up 60– 70% of the volume of the islets. Glucagon is synthesised and stored in the A cells (10–20% of the islets). Somatostatin is synthesised and stored in the D cells (5–10% of the islets).

Equivalent dose of prednisolone vs hydrocortisone therapy is usually about 25% of the hydrocortisone dose. Adequacy of steroid replacement is normally assessed by clinical well being and restoration of normal (not excessive) weight. Cortisol levels during the day are only a useful assessment if the patient is on hydrocortisone. Patients normally require therapy with mineralocorticoids as well as glucocorticoid therapy. Standard therapy is with fludrocortisone 50–300 mg/day, and effectiveness is assessed by serum electrolytes, postural change in blood pressure, and suppression of plasma renin activity to normal levels. Kallmann’s syndrome is due to isolated gonadotrophin-releasing hormone (GnRH) deficiency. It is often familial and X-linked. Klinefelter’s syndrome is also associated with hypogonadism, but the other clinical features are not seen. Cryptorchidism is ruled out by the presence of testes in the scrotum. The features are not suggestive of mumps orchitis or hyperprolactinaemia. which of the following hormones is under continuous inhibition? The answer is (a). Prolactin is under predominantly inhibitory control, by levels of dopamine. Prolactin levels are known to rise during pregnancy, lactation, severe stress, sleep and coitus. Mildly increased prolactin levels in the range of 400–600 mU/litre may be physiological, but higher levels require a diagnosis. Levels above 1000 imply the possibility of a microprolactinoma, and levels above 5000 imply the presence of a macroprolactinoma. Drug causes of hyperprolactinaemia are, not surprisingly, the dopamine antagonists, which include metoclopramide, domperidone and the phenothiazines. Features of hyperprolactinaemia in women include amenorrhoea, galactorrhoea, loss of libido, subfertility and features of androgen deficiency.